Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][CH:10]2[O:14][CH2:13][CH2:12][O:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1.[O:22]=[CH:23][C:24](OCC)=O.O>C(O)C.C(OCC)(=O)C>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][N:8]1[C:23](=[O:22])[CH:24]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)C=O
Reactant: Nc1cccnc1NCC1OCCO1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cnc2cccnc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.20 g of 3-amino-2-(1,3-dioxolan-2-ylmethyl)aminopyridine in 2 mL of ethanol, 0.25 g of a 45 to 50% toluene solution of ethyl oxoacetate was added, and the mixture was heated under reflux while stirring for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, and thereto were added water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=100:0 to 90:10 to obtain 0.16 g of 4-(1,3-dioxolan-2-ylmethyl)pyrido(2,3-b)pyrazin-3(4H)-one as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:24][C:25]#[N:26])[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)[CH:12]=2)[N:5]2[CH:27]=[CH:28][N:29]=[C:4]2[CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].O1CCOCC1>[C:25]([CH2:24][C:13]1([N:11]2[CH:12]=[C:8]([C:6]3[N:5]4[CH:27]=[CH:28][N:29]=[C:4]4[CH:3]=[C:2]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=4)[N:7]=3)[CH:9]=[N:10]2)[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)#[N:26]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(Cl)cc4nccn34)cn2)C1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc4nccn34)cn2)C1
Temperature: 75 °C

Procedure:
To a vial charged with tert-butyl 3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (Preparation N; 490 mg; 1.18 mmol); 4-(trifluoromethyl)phenylboronic acid (337 mg; 1.78 mmol); Pd2dba3 (108 mg; 0.118 mmol); XPHOS (113 mg; 0.237 mmol) and potassium phosphate (3.55 mmol; 2M aqueous solution) was added 1,4-dioxane (10 mL). The mixture was sparged with nitrogen for 15 minutes. The vial was then sealed and heated for 3 hours at 75° C. with magnetic stirring. The mixture was diluted with methylene chloride (20 mL) and aqueous sodium bicarbonate solution (20 mL) was added. The mixture was extracted into methylene chloride (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting materiel was triturated with ether and the solids were collected and dried under vacuum to give the desired product as an off white solid (410 mg). MS (apci) m/z=524.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].C(N(CC)CC)C.[C:25]1([C:31](Cl)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCCCCCC>O1CCCC1>[CH3:7][N:6]1[C:2]([NH:1][C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:3]([NH:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:4]=[N:5]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)Oc2ccccc2)c1N
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)Oc2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 6.5 h
Yield: 80.7 %

Procedure:
To a suspension of 5-amino-1-methyl-4-phenoxycarbonylaminopyrazole (153.8 g) in tetrahydrofuran (1 L) were added triethylamine (67 g) and triphenylmethyl chloride (185 g) at room temperature. The mixture was stirred for 6.5 hours. To the reaction mixture was added heptane (2.6 L) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and washed with heptane-diisopropyl ether (1:1). The crude solid was suspended in water (3 L) and the suspension was stirred for 1 hour. The solid was collected by filtration and dried to give 1-methyl-4-phenoxycarbonylamino-5-triphenylmethylaminopyrazole (253.6 g).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:24])[C:18]([NH:21][CH2:22][CH3:23])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:32](=N)(OCC)[CH3:33]>C(O)(=O)C>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[N:21]([CH2:32][CH3:33])[C:22]([CH3:23])=[N:24][C:17]=4[CH:16]=3)[CH2:12][CH2:13]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(C)=N
Reactant: CCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Agent: Cl
Solvent: CC(=O)O
Product: CCn1c(C)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4.8 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -ethyl-1,2-benzenediamine and 25 parts of acetic acid is stirred at room temperature till all solid enters solution. Then there are added 1.73 parts of ethyl ethanimidate hydrochloride and stirring is continued first for one hour at room temperature and further for one hour at reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with a sodium hydroxide solution and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2.7 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-2-methyl-1H-benzimidazole; mp. 152.9° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]>CS(C)=O>[Si:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:1]#[N:2])([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCC#N
Temperature: 90 °C
Reaction time: 1.67 h

Procedure:
Sodium cyanide (1.2 g) dissolved in dimethylsulphoxide was heated at 90° C. for 30 min. Solid 1-t-butyldimethylsilyloxy-6-bromohexane (5.8 g, compound X1) prepared according to the method previously described (ref. 37), then was added into the sodium cyanide solution. After heating at 120°-130 C. for 20-180 min, the reaction mixture was poured into ice-cold water and the aqueous layer was extracted with ether, washed with brine, dried and concentrated. The product was distilled at 0.5 Torr and 107° C. to give a colourless oil. High resolution mass spectrometer for C12 H24 O N Si: calculated 226.1627, found 226.1624.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[CH2:8][C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2].[Li][CH2:28]CCC.CCCCCC.CI>C1COCC1>[CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[CH:8]([CH3:28])[C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1C(=O)Cc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCC(CC)N1C(=O)C(C)c2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a −78° C. solution of 1-(1-ethyl-propyl)-6-methyl-4-(2,4,6-trimethyl-phenoxy)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (352 mg, 1.0 mmol) in 2 ml of dry THF was added 2.5M BuLi in hexane (0.4 mmol, 1.0 mmol). The resulting mixture was stirred at −78° C. for 30 min, then transferred to a −78° C. solution of methyl iodide (3 ml) in 3 ml of dry THF. The resulting mixture was stirred at −78° C. for 1 hour, quenched with saturated ammonium chloride, extracted with ethyl acetate. The organic layer was dried and concentrated to give a clear oil which was purified through silica gel column chromatography using hexane to 10% ethyl acetate in hexane as eluent to give the title compound as tan solid 214 mg (68%). 1H NMR (CDCl3) δ 6.88 (s,2H), 6.47(s,1H), 4.1(m,1H), 3.56(q,1H), 2.30(s,3H), 2.26(s,3H), 2.07(s,6H), 1.7–2.0(m,4H), 1.60(d,3H), 0.86(t,6H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[C:6]([Cl:8])[Cl:7])C.O1CCCC1.[OH-].[Li+].Cl>O>[Cl:7][C:6]([Cl:8])=[C:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=C(Cl)Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
P1.2): 650 mg of 3,3-dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid ethyl ester are introduced into 4 ml of tetrahydrofuran. 100 mg of lithium hydroxide in 1.5 ml of water are then added and the mixture is stirred at room temperature for 16 hours. After a further 4 hours at 40° C., the reaction mixture is poured into water, rendered acidic with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phases are washed twice with water and concentrated. 3,3-Dichloro-2-(4-trifluoromethyl-phenyl)-acrylic acid is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:20][C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)=[N:23][CH:22]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:29][C:28]2[CH:31]=[CH:32][N:33]=[C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][N:23]=3)[CH:27]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: Cc1cnc(-c2cc(C=O)ccn2)s1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 2-(5-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 412.01 g/mol.
Reaction SMILES: N[C:2]1[N:6](C2C(Cl)=CC(C(F)(F)F)=CC=2Cl)[N:5]=[C:4](C#N)[CH:3]=1.[F:21][C:22]([F:33])([F:32])[S:23]([N:25]1C(=O)CCC1=O)=[O:24]>C(N(CC)CC)C>[F:21][C:22]([F:33])([F:32])[S:23]([NH:25][N:6]1[CH:2]=[CH:3][CH:4]=[N:5]1)=[O:24]
Reactant: O=C1CCC(=O)N1S(=O)C(F)(F)F
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Solvent: CCN(CC)CC
Product: O=S(Nn1cccn1)C(F)(F)F

Procedure:
In EP-A 1 331 222, 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (II) is sulfinylated using N-trifluoromethylsulfinylsuccinimide as the sulfinylating agent in the presence of triethylamine and without the addition of a chlorinating agent. The intermediate N-trifluoromethylsulfinylamino-pyrazole is isolated and under the conditions of a Thia-Fries rearrangement transformed into the final product 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(trifluoromethylsulfinyl)-pyrazole-3-carbonitrile.
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH2:10]([N:6]([CH2:7][CH3:8])[CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH3:3])[CH3:9]
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Reactant: c1cn[nH]c1
Product: CCN(CC)C[C@@H](C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N,N-diethyl-1,2-propanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[CH:10]=[N:11][C:12]([NH2:26])=[C:13]([O:14][C@@H:15]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[Cl:25])[CH3:16])[C:8]=2[O:7][CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:26][C:12]1[N:11]=[CH:10][C:9]2[C:5]([CH2:3][OH:2])=[CH:6][O:7][C:8]=2[C:13]=1[O:14][C@@H:15]([C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=1[Cl:25])[CH3:16]
Reactant: COC(=O)c1coc2c(O[C@H](C)c3c(Cl)ccc(F)c3Cl)c(N)ncc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1c(N)ncc2c(CO)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C

Procedure:
To a solution of 6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-3-carboxylic acid methyl ester (140 mg, 0.35 mmol) in THF (5 mL) was added 0.7 mL of LiAlH4 (1M solution in THF, 0.7 mmol) at 0° C. under nitrogen. The mixture was slowly warmed to rt. The reaction was quenched with EtOAc (25 mL), then water (1 mL). The organic phase was separated and washed with brine (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (Hex:EtOAc=50:50→100% EtOAc) to give the title compound as a white solid. LC-MS (ES+): 370.95/372.94 [MH+]. 1H NMR (CDCl3, 400 MHz): δ 1.66 (br s, 1H), 1.86 (d, J=6.6 Hz, 3H), 4.73 (br s, 2H), 4.79 (s, 2H), 6.53 (q, J=6.8 Hz, 1H), 7.04 (m, 1H), 7.27 (m, 1H), 7.37 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][O:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccncc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-hydroxypyridine (10 g, 105 mmol), ethyl 4-bromobutyrate 12-1 (15.0 ml, 105 mmol) and Cs2CO3 (34.2 g, 105 mmol) in DMF (100 ml) was stirred at room temperature for 24 h. The reaction was filtered and the filtrate diluted with ethyl acetate (300 ml) and washed with water (4×100 ml) and brine (100 ml) then dried (Na2SO4), filtered, and evaporated. The resulting oil was purified by chromatography on silica gel (3% CH3OH/CH2Cl2) to give 12-2 as a colorless glass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39]O)=[CH:37][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:39][C:36]5[CH:35]=[CH:34][C:33]([O:32][CH3:31])=[CH:38][CH:37]=5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COC(=O)c2ccc3c(c2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)cc1

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and p-methoxybenzyl alcohol. Yellow solid, 194 mg. ES-MS m/z 540 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].IC.[C:26](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[O:15][CH3:26])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)c2c(Oc3ccccc3)cccc2c1OC
Temperature: 45 °C
Yield: 52.3 %

Procedure:
A mixture of 1-bromo-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (1.89 g, 5.07 mmol), iodomethane (632 μL, 10.13 mmol), cesium carbonate (3.3 g, 10.13 mmol) and dimethylformamide (15 mL) was stirred at 45° C. for sixteen hours before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, concentrated in vacuo and the residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow solid (1.03 g): MS: (+) m/z 387.64, 389.75 (M+1, 79Br/81Br).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]OS(C)(=O)=O)=[N:6][CH:7]=1.[N-:14]=[N+]=[N-].[Na+]>CN(C=O)C.CCCCCC.CCOC(C)=O>[NH2:14][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1ccc(F)cn1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCc1ccc(F)cn1
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Dissolve methanesulfonic acid (5-fluoro-pyridin-2-yl)-methyl ester (1.5 g, 7.3 mmol) in DMF (5 mL) and add sodium azide (950 mg, 14.6 mmol). Stir the mixture for 30 min, then dilute with hexane/EtOAc (1:1, 50 mL). Wash the mixture with 10% aqueous NaCl (3×10 mL). Dry the combined organic extracts over Na2SO4 and remove half of the solvent in vacuo. Add EtOAc (20 mL) and a suspension of 10% Pd/C (200 mg) in EtOAc (2 mL). Stir the mixture for 1 h at ambient temperature in a pressurized vessel under 50 psi of hydrogen. Filter the slurry through Celite® and concentrate in vacuo to obtain 2-aminomethyl-5-fluoro-pyridine (613 mg, 60% yield, 80% purity by GC/MS). GC-MS m/z: 126 (M+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][CH:10]2[CH:15]([OH:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]3[CH:19]=[CH:20][S:21][C:11]2=3)=[O:8])=[CH:5][CH:4]=1>Cl(O)(=O)(=O)=O.C(OC(=O)C)(=O)C>[C:7]([O:16][CH:15]1[C:14]([CH3:18])([CH3:17])[O:13][C:12]2[CH:19]=[C:20]([C:12](=[O:13])[CH3:11])[S:21][C:11]=2[CH:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:24])[F:25])=[CH:23][CH:22]=1)(=[O:8])[CH3:6]
Reactant: CC1(C)Oc2ccsc2C(NC(=O)c2ccc(C(F)(F)F)cc2)C1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1C(NC(=O)c2ccc(C(F)(F)F)cc2)c2sc(C(C)=O)cc2OC1(C)C

Procedure:
The title compound was prepared as described in Example 6 starting with 7-(4-trifluoromethylbenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.5 g, 4.04 mmol), perchloric acid (70%, 10 drops) and acetic anhydride (20ml) to give the product after crystallization from dichloromethane and hexanes 0.382 g (21%) as a colorless solid; mp 225°-227° C.; IR (KBr):1755, 1668, 1654, 1541 and 1471 cm-1 ; MS=m/z 456 (MH+);1H NMR (CDCl3): δ 1.41(s,3H), 1.43 (s,3H), 2.13 (s,3H), 2.47 (s,3H), 5.17 (d,J=9.3 Hz,1H), 5.42(m,1H), 6.77 (bd,J=7.9 Hz,1H), 7.14 (s,1H), 7.72 (d,J=8.3 Hz, 2H) and 7.88 (d,J=8.3 Hz,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19]12([CH:26]([CH3:30])[C:27](Cl)=[O:28])[O:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:27](=[O:28])[CH:26]([C:19]34[O:25][CH:22]([CH2:23][CH2:24]3)[CH2:21][CH2:20]4)[CH3:30])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CC(C(=O)Cl)C12CCC(CC1)O2
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C(C)C34CCC(CC3)O4)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine and 2-(7-oxa-bicyclo[2.2.1]hept-1-yl)-propionyl chloride, the title compound was obtained as white solid (67% yield). MS: m/e=418(M+H+), mp 195-197° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[CH:4][CH:3]=1.ONC(C1C2C=CNC=2C=CC=1)=N.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][CH3:39])[C:31](O)=O)[CH3:26].C(OC1C=C(C=CC=1OCCC)C(O)=O)CC>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:9]=[C:31]([C:30]3[CH:34]=[CH:35][C:36]([O:37][CH2:38][CH3:39])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[O:8][N:7]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1ccc(Br)cc1
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Agent: CCCOc1ccc(C(=O)O)cc1OCCC
Agent: N=C(NO)c1cccc2[nH]ccc12
Product: CCOc1ccc(-c2nc(-c3ccc(Br)cc3)no2)cc1OCC
Yield: 58 %

Procedure:
When the product of Step A was substituted for N-hydroxy-1H-indole-4-carboximidamide and 3,4-diethoxybenzoic acid was substituted for 3,4-dipropoxybenzoic acid in Example 43, Step C the similar process afforded the title compound in 58% yield. 1H-NMR (CDCl3) 1.47-1.53 (m, 6H); 4.14-4.24 (m, 4H); 6.97 (d, 1H, J=8.48 Hz); 7.61-7.66 (m, 3H); 7.77 (dd, 1H, J=1.98, 8.42 Hz); 8.00 (d, 2H, J=8.55 Hz).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[N:7]=[C:6]([S:8][C:9]2[N:13]=[CH:12][N:11]([C:16](=[O:17])[N:15]([CH3:19])[CH3:14])[N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc(Sc2nc[nH]n2)n1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)n1cnc(Sc2cccc(Br)n2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(6-bromo-2-pyridyl)thio-1H-1,2,4-triazole (73 mg), dimethylcarbamoyl chloride (40 μl), anhydrous potassium carbonate (80 mg) and N,N-dimethylformamide (0.5 ml) was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate-water. The organic layer was washed with water, followed by saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica-gel column chromatography with 20% (20% 2-propanol/ethyl acetate)/hexane to yield the title compound (77 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1.COCO[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1>CO>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[OH:24])[CH2:6]1
Reactant: COCO[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: COCO[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Solvent: CO
Product: COCO[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1

Procedure:
1.1 g. of 3β-methoxymethoxy-5-androsten-17-one is hydrogenated as disclosed in Example 25. The thus-obtained crude product is not quite uniform and contains, in addition to 3β-methoxymethoxy-5α-androstan-17-one, of which 0.65 g. can be obtained by crystallization from methanol, also proportions of 3β-methoxymethoxy-5α-androstan-17β-ol. By continuing the hydrogenation or by reduction with sodium borohydride, this product becomes the primary yield.