Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH2:28][CH3:29])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:19][CH2:18][C@@H:17]([O:20][CH3:21])[CH2:16]3)[CH:12]=[CH:11][C:10]=2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:5][CH2:4]1)[CH3:2].[CH:30](=O)[CH2:31][CH2:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:30]([N:25]1[CH2:24][CH2:23][N:22]([C:10]2[CH:11]=[CH:12][C:13]([N:15]3[CH2:19][CH2:18][C@@H:17]([O:20][CH3:21])[CH2:16]3)=[CH:14][C:9]=2[CH:6]2[CH2:7][CH2:8][C:3]([CH2:1][CH3:2])([CH2:28][CH3:29])[CH2:4][CH2:5]2)[CH2:27][CH2:26]1)[CH2:31][CH2:32][CH3:33]
Reactant: CCC1(CC)CCC(c2cc(N3CC[C@@H](OC)C3)ccc2N2CCNCC2)CC1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCN1CCN(c2ccc(N3CC[C@@H](OC)C3)cc2C2CCC(CC)(CC)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a mixture of the crude product of (R)-1-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine produced in Example (98b) (160 mg), butyraldehyde (0.052 mL, 0.584 mmol) and tetrahydrofuran (7 mL) were added sodium triacetoxyborohydride (164 mg, 0.774 mmol) and acetic acid (0.022 mL, 0.384 mmol) in that order, followed by stirring for 1 hour at room temperature. Ethyl acetate and saturated aqueous solution of sodium hydrogencarbonate were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 170 mg of (R)-1-butyl-4-[2-(4,4-diethylcyclohexyl)-4-(3-methoxypyrrolidin-1-yl)phenyl]piperazine as a light brown oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:24]2[CH2:25][CH2:26][CH:22]([C:19]3[CH:20]=[CH:21][C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:17][CH:18]=3)[CH2:23]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C2CCNC2)cc1
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(C2CCN(C3CCC(C(C)(C)C)CC3)C2)cc1

Procedure:
15.4 g (100 millimoles) of 4-tert-butylcyclohexanone, 9.8 g (48 millimoles) of 3-(4-tert-butylphenyl)-pyrrolidine, 6.8 g (50 millimoles) of zinc(II) chloride and 6.3 g (100 millimoles) of sodium cyanoborohydride in 200 ml of absolute methanol were stirred for 48 hours at 22° C. The methanol was distilled off under reduced pressure and the residue was dissolved in dichloromethane and 5% strength sodium hydroxide solution.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]([OH:16])=[O:15])[CH:8]=2)[O:3]1.C(OC1C=CC(O)=CC=1C(C)(C)C)(=O)C.[C:33]([O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([CH3:36])([CH3:35])[CH3:34].C(OCC)(=O)C>S(Cl)(Cl)=O.CCCCCC>[C:33]([O:37][C:38]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([O:15][C:14]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]3([CH3:12])[CH3:13])=[O:16])=[CH:44][CH:45]=1)=[O:47])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Reactant: CC1(C)CC(C)(C)c2cc(C(=O)O)ccc2O1
Agent: CC(=O)Oc1ccc(O)cc1C(C)(C)C
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 2,2,4,4-tetramethyl chroman-6-carboxylic acid (0.1 g, 0.43 mmol) in thionyl chloride (10 mL) was refluxed for 2 h. The thionyl chloride was evaporated under reduced pressure and the residue was dissolved in 5 mL of dichloromethane and treated with triethyl amine (5 mL) followed by tert-butyl-4-hydroxy phenyl acetate (Reagent E, 0.088 g, 0.427 mmol). After 0.5 h, the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent to afford the title compound (0.1 g, 55%).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Br[CH:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:14]=O.CCOCC>CCO>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CC(Br)CC(F)(F)F
Reactant: COc1ccnc(N)c1C#N
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Temperature: 156 °C
Yield: 19 %

Procedure:
A mixture of compound D3 (3.31 g, 22.19 mmol) and D4 (6.2 g, 21.86 mmol) in EtOH (10 ml) was subjected to microwave heating at 156° C. for 40 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was treated with Et2O and a solid precipitated. The solid was filtered off, washed with EtOAc and dried in vacuo to yield compound D5 (1 g, 18%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9]O)[S:7][CH:8]=1)([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.[H-].[Na+].[CH:31]1([N:34]2[C:43]3[C:38](=[CH:39][C:40]([F:45])=[C:41](F)[CH:42]=3)[C:37](=[O:46])[C:36](/[CH:47]=[CH:48]/[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:35]2)[CH2:33][CH2:32]1.[Cl-].[NH4+]>CN(C)C=O>[CH:31]1([N:34]2[C:43]3[C:38](=[CH:39][C:40]([F:45])=[C:41]([CH2:9][C:6]4[S:7][CH:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:5]=4)[CH:42]=3)[C:37](=[O:46])[C:36](/[CH:47]=[CH:48]/[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:35]2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(C)c1csc(CO)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)c1csc(Cc2cc3c(cc2F)c(=O)c(/C=C/C(=O)OC(C)(C)C)cn3C2CC2)n1
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
(4-Isopropyl-1,3-thiazol-2-yl)methanol (19.5 mg, 0.124 mmol) was dissolved in dimethylformamide (1 ml), added with 18-crown-6 (35.8 mg, 0.135 mmol) and sodium hydride (95%, 3.4 mg, 0.135 mmol), and stirred for 15 minutes under argon atmosphere. The reaction mixture was added with a solution of tert-butyl (E)-3-(1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolyl)-2-propenoate (39.2 mg, 0.124 mmol) in dimethylformamide (1 ml) and stirred at room temperature for 3 hours. Then, the reaction mixture was added with aqueous ammonium chloride and extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=100:1) to obtain the title compound (44.7 mg, 82%).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=NNC(N)=O.[OH-].[K+].Cl>C(O)COCCO.O>[CH3:13][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([OH:12])[C:2]=1[OH:1]
Reactant: NC(=O)NN=Cc1c(O)c(O)cc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1c(O)c(O)cc2ccccc12
Yield: 66.1 %

Procedure:
131 g of 2,3-dihydroxy-naphthaldehyde semicarbazone were boiled at reflux overnight with 250 g of powdered potassium hydroxide in 1350 ml of diethyleneglycol under an argon stream in a 1.5 l sulfonation flask equipped with stirrer, condenser, theremometer and calcium chloride tube. The cooled solution was diluted with 4,5 l of water, made acid with 450 ml of concentrated hydrochloric acid and extracted eight times with 1 l ether. The combined ether extracts were dried over sodium sulfate and evaporated in vacuo. Recrystallization from water gave 61.5 g (65.5% of theory) of 1-methyl-2,3-dihydroxy-naphthalene. Melting point 97°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:4][N:3]=1.[N+:14]([NH:17][C:18](N)=N)([O-:16])=[O:15]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][NH:13][C:18]2=[N:17][N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: N=C(N)N[N+](=O)[O-]
Reactant: NCCCNCc1ccc(Cl)nc1
Solvent: O
Product: O=[N+]([O-])N=C1NCCCN1Cc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 45.2 %

Procedure:
A solution composed of N-(2-chloro-5-pyridylmethyl)trimethylenediamine (10 g), nitroguanidine (5.7 g) and water (80 ml) was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and extracted twice with 50 ml of dichloromethane. Dichloromethane was distilled off from the extracts, and the tarry residue was purified by silica gel column chromatography to give almost colorless 1-(2-chloro-5-pyridylmethyl)-2-(nitroimino)tetrahydropyrimidine (6.1 g). mp. 113°-117° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:14][C:15](OC(C)(C)C)=[O:16]>C1COCC1.C(OCC)C>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:14][CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)CN(c1ccccn1)c1ccccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCN(c1ccccn1)c1ccccn1
Temperature: 25 °C

Procedure:
To a slurry of LAH (lithium aluminum hydride) (1.17 g, 30.8 mmol, 3.0 equiv) in THF (tetrahydrafuran) (45 ml) was added Tert-butyl 2-(di(pyridine-2-yl)amino)acetate (2.9 g, 10.2 mmol) at 0° C. under 1 atm argon (Ar). The reaction was slowly warmed to room temperature over 4 h. The reaction mixture was then diluted with diethyl ether and cooled to 0° C. The reaction was quenched via careful addition of water (4.0 ml) and then dried with magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by flash chromatography (SiO2, hexane/ethyl acetate=1:1) to afford DPAE as a pale yellow oil. DPAE was obtained (Yield: 1.2 g (55%)), and confirmed by 1H NMR (DMSO-d6, 300 MHz): δ8.27 (m, 2H), 7.62 (m, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.93 (m, 2H), 4.92 (t, J=5.4 Hz, 1H), 4.16 (t, J=6.5 Hz, 2H), 3.58 (q, J=6.5 Hz, 2H). ESI-MS (cation): 216.1 m/z (M+H+) obsd, 215 m/z calcd.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[P:34](=[O:51])(Cl)([S:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:34](=[O:51])([S:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([O:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[C:13]2[C:4](=[CH:5][C:6]3[C:11]([N:12]=2)=[CH:10][C:9]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:8][CH:7]=3)[CH:3]=1)[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1
Reactant: CS(=O)(=O)c1ccc2cc3cc(O)cc(C#N)c3nc2c1
Reactant: O=P(Cl)(Oc1cccc(Br)c1)Sc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2cc3cc(OP(=O)(Oc4cccc(Br)c4)Sc4ccccc4)cc(C#N)c3nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-4-cyano-6-methylsulfonylacridine (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(3-bromophenyl) S-phenyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then wasshed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(3-bromophenyl) O-(4-cyano-6-methylfulfonylacridin-2-yl) S-phenyl phosphorothioate.
Reaction SMILES: [CH:1]([NH:4][C@H:5]([C:12]([OH:14])=O)[CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)([CH3:3])[CH3:2].[NH2:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C[O-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)C>[CH2:32]([O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:16]([NH:15][C:12](=[O:14])[CH:5]([NH:4][CH:1]([CH3:2])[CH3:3])[CH2:6][C:7]2[N:11]=[CH:10][NH:9][CH:8]=2)[C:17](=[O:18])[NH:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:26][CH:27]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)NC(Cc1c[nH]cn1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 3 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A solution of N-isopropylhistidine (302 mg, 1.53 mmol), (S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (500 mg, 1.32 mmol), and benzyltrimethylammonium methoxide (40% solution in methanol, 2.1 mL, 3.36 mmol) in 10 mL dry DMF was cooled to 3° C. Then, HBTU (581 mg, 1.53 mmol) was added and the resulting mixture stirred at 3° C. for 60 minutes, warmed to 25° C., diluted with 35 mL diethyl ether, and washed with saturated aqueous sodium bicarbonate solution (35 mL) as well as with brine (35 mL), dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The residue thus obtained was further purified twice by silica gel chromatography using 10% methanol in chloroform as eluant, to give 122 mg (13%) of the title compound as the dihydrochloride salt.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH:17]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C:12]([O:14]C)=[O:13].O1CCCC1.CO.O>C(O)(=O)C>[F:3][C:4]1[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:33])[C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])[CH:17]=2)[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)c(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
100 mg (2.5 mmol, 8 eq) of sodium hydroxide are added to a solution of 130 mg (0.3 mmol, 1 eq) of methyl 3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate in 3 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred for 3 hours at room temperature. The reaction is stopped by addition of 10 mL of water and 1 mL of acetic acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). The oil obtained is crystallized from heptane/dichloromethane. 55 mg of 3-[3-fluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid in the form of a white solid are obtained (m.p.=92-93° C.). Yield=43%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CC(=O)OCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:10])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(Cl)ncc1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 2,5-dichloro-4-hydroxypyridine (1.43 g, 8.73 mmol) in DMF (15 mL), K2CO3 (2.41 g, 17.5 mmol) followed by methyl iodide (1.48 g, 8.73 mmol) is added. The mixture is stirred at rt for 24 h before it is diluted with EA (200 mL), washed with water (2×100 mL), dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 2,5-dichloro-4-methoxy-pyridine (0.73 g) as a white solid; LC-MS: tR=0.85 min; [M+1]+=177.90.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41])[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:37][C:35]([F:36])([F:38])[C:33]1[CH:32]=[C:31]([C:39]([CH3:44])([CH3:43])[C:40]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[CH3:9])=[O:41])[CH:30]=[C:29]([C:28]([F:27])([F:45])[F:46])[CH:34]=1
Reactant: CNc1cnc(Cl)cc1-c1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To a solution of 20 g (79 mmol) [6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-methyl-amine in 200 ml tetrahydrofuran were added dropwise at 0° C. 113 ml (94.8 mmol) of a 0.91 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran. The reaction mixture was stirred at room temperature for 30 min. After cooling to 0° C. 27.7 g (86.9 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The reaction mixture was treated with 220 ml 1 N sodium hydrogencarbonate solution and extracted with three 200-ml portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and triturated with 150 ml diethylether to give 34.6 g (82%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[N-:34]=[N+:35]=[N-:36].[Na+].CN(C)C=O>CO.O>[N:34]([CH2:2][C:3](=[O:33])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:32])[C@@H:14]([N:24]4[CH2:29][CH2:28][O:27][C:26]([CH3:31])([CH3:30])[CH2:25]4)[CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CCl)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CN=[N+]=[N-])[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Yield: 34.7 %

Procedure:
A stirred mixture of (2β,3α,5α)-21-chloro-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (500 mg), sodium azide (140 mg), N,N-dimethylformamide (1.25 ml) in methanol (10 ml) and water (0.25 ml) was heated under reflux for 2 h, then cooled and poured into water (50 ml). The resulting precipitate was filtered off and dissolved in dichloromethane. After washing the solution with water and drying over sodium sulfate, the solvent was removed under reduced pressure and the residue (422 mg) was chromatographed on silica gel. The purified product was crystallised from dichloromethane-methanol to give (2β,3α,5α)-21-azido-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (176 mg). δ (CDCl3) 0.62 (s,3H), 1.06 (s,3H), 1.22 (s,3H), 1.24 (s,3H) and 3.85 (s,2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:15])[CH:8]=2)[N:3]=1.C[Si]([N-:20][Si](C)(C)C)(C)C.[Li+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[F:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:20])[N:11]=[C:10]2[N:12]([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN(C)c1nc(Cl)nc2ccc(F)cc12
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1nc(N)nc2ccc(F)cc12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 8818.2 %

Procedure:
A stirring mixture of (2-chloro-6-fluoro-quinazolin-4-yl)-dimethylamine (50 mg, 0.22 mmol), lithium bis(trimethylsilyl)amide (260 μL, 0.26 mmol, 1.0 M in hexanes), Pd2(dba)3 (20 mg, 0.022 mmol), 2-(dicyclohexyl)phosphinobiphenyl (19 mg, 0.053 mmol), and THF (1.0 mL) was heated in a sealed tube via microwave irradiation at 65° C. for 1.5 hours. 1.0 N aqueous HCl solution (3.0 mL) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between H2O and EtOAc. The organic portion was evaporated to dryness under reduced pressure. The obtained residue was purified via silica gel chromatography using 95% CH2Cl2/5% MeOH to obtain the desired amine as a tan solid (40 mg, 19.4 mmol, 88% yield). LC/MS (10-99%) M/Z 206.9 retention time 1.18 min.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH2:29])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:2]1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][OH:54])[CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[CH2:2]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]2[N:13]3[CH:14]=[C:15]([O:18][C@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:22]([NH:29][C:34]([NH:35][C:36]5[N:37]([C:45]6[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:52][CH2:53][OH:54])[CH:46]=6)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=5)=[O:33])[CH2:21][CH2:20]4)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)[CH2:1]1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Reactant: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCCC45CC5)n3c2)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCCC56CC6)n4c3)c3ccccc32)n(-c2cccc(OCCO)c2)n1
Yield: 89.2 %

Procedure:
An orange-brown solution of Intermediate 148d (87.2 mg, 0.224 mmol), Intermediate 148e (100 mg, 0.224 mmol) and DIPEA (0.049 mL, 0.28 mmol) in dry dioxane (3 mL) was stirred at 75° C. for 16 h. The cooled solution was concentrated in vacuo, suspended in water (5 mL) and extracted with DCM (2×5 mL). The combined organics were passed through a hydrophobic frit and concentrated in vacuo to leave a brown gum. Flash chromatography (silica 12 g, 4-8% MeOH in DCM) gave the title compound as a pale yellow solid (138 mg, 89%). LCMS (Method 3): Rt 3.57 min, m/z 691 [MH+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc2c(c1)CCc1ccccc1N2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)CCc1ccccc1N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of 1.0 g of Compound 31-2a, 1.5 g of imidazole, 1.5 g of tert-butyldimethylsilyl chloride and 30 ml of DMF was stirred overnight at room temperature, followed by addition of ice chips and further stirring. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate (10/1)]to give 1.34 g (89%) of the product as a colorless oily substance.