Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH3:15]S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O
Reactant: O=C(O)c1ccc2cc(Br)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2cc(Br)ccc2n1
Temperature: 20 °C
Reaction time: 8 h
Yield: 325 %

Procedure:
A mixture of 6-bromo-2-quinolinecarboxylic acid (331 g, from multiple batches, 1.31 mol) and methanesulfonic acid (22 mL, 33 g, 0.34 mol) in methanol (2 L) was refluxed for 6 hr. The mixture was treated with a solution of sodium bicarbonate (29 g, 0.34 mol) in water (350 mL) and the resulting suspension was slowly cooled to 20° C. and stirred overnight. The suspension was filtered and the cake was washed with water (1 L). The solid was dried in a vacuum oven at 50° C. for 3 days to yield methyl 6-bromo-2-quinolinecarboxylate (294 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=9 Hz, 1H), 8.40 (d, J=2 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 8.08 (d, J=9 Hz, 1H), 7.97 (m, 1H), 3.93 (s, 3H). ES-LCMS m/z 267 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[C:3]=1[F:23].C([Li])CCC.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:23][C:3]1[C:4]2[O:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:5]=2[CH:21]=[CH:22][C:2]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: Fc1c(Br)ccc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1F)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-4-fluoro-2,2-diphenyl-1,3-benzodioxol (17.3 g) are dissolved in 150 ml of tetrahydrofuran, treated at -78° C. with 29.1 ml of a 0.6M solution of n-butyllithium in n-hexane and stirred at -78° C. for 15 minutes. Thereupon, 10 ml of dimethylformamide are added, after stirring for a further 15 minutes the mixture is treated with semi-saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried with magnesium sulphate and evaporated. The residue is crystallized from ethanol. After drying there are obtained 12.7 g of 4-fluoro-2,2-diphenyl-1,3-benzodioxol-5-carboxaldehyde as white crystals of m.p. 92°-94° C.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[CH3:26][C@H:27]1[O:32][CH2:31][CH2:30][NH:29][C@@H:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:30][CH2:31][O:32][C@H:27]([CH3:26])[C@H:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Product: COC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 51.7 %

Procedure:
Methyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.85 g, 1.9 mmol) was reacted with (2R,3S)-2-methylmorpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34 to give the title compound as a yellow solid (0.5 g, 52%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:18][CH:17]=1.[H-].[Na+]>CN(C=O)C.CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]([CH2:31][CH2:32][CH3:33])[C:23]2=[O:34])=[CH:20][CH:21]=1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Temperature: 180 °C
Yield: 50.4 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (320 mg) was added to a solution of 3-(4-hydroxyphenyl)-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (400 mg) and NaH (65.3 mg) in DMF (5 mL) at 100° C. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1-propyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (300 mg) as white crystals.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[CH3:17][S:18]([NH:21][C:22]1([C:25]2[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)(=[O:20])=[O:19].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:28]3[CH:27]=[CH:26][C:25]([C:22]4([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])[CH2:24][CH2:23]4)=[CH:30][CH:29]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: CS(=O)(=O)NC1(c2ccc(B(O)O)cc2)CC1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC1(c2ccc(Oc3ccc4c(c3)S(=O)(=O)NC3CCCN43)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension composed of 290 mg (1.21 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 465 mg (1.82 mmol) of the compound obtained in Step D, 330 mg (1.82 mmol) of copper(II) acetate, 294 μl (3.64 mmol) of pyridine and about 3.5 g of 4 Å molecular sieve in 35 ml of CH2Cl2 is stirred for 5 hours at ambient temperature. The reaction mixture is filtered and rinsed with CH2Cl2/MeOH (1/1). The filtrate is concentrated and then directly applied to a silica column, eluting with a mixture of CH2Cl2/acetone 96/4. The fractions containing the expected compound are collected and evaporated and the residue is taken up in a small amount of ethyl ether. After filtering off the solid, the title compound is collected in the form of a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:34][CH3:35])=[C:16]([CH:23]4[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.FC(F)(F)C(O)=O>C(Cl)Cl.CO.C(=O)(O)[O-].[Na+].[Cl-].[Na+].O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17]([C:21]#[N:22])=[C:16]([CH:23]4[CH2:24][NH:25][CH2:26]4)[C:15]=3[O:34][CH3:35])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.6 %

Procedure:
A solution of tert-butyl 3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-methoxyphenyl}azetidine-1-carboxylate (1.7 g, 3.3 mmol) in methylene chloride (30 mL) was treated with trifluoroacetic acid (20 mL) and stirred at room temperature for 20 min. The reaction mixture was concentrated to give a residue that was diluted with methanol (50 mL) and saturated sodium bicarbonate solution (50 mL). This aqueous solution was diluted with brine (50 mL) and extracted with a 5:1 mixture of dichloromethane/isopropanol (5×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give the desired product (1.4 g, 97%). The product was isolated as a single enantiomer. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.46 (s, 1H), 7.34 (br s, 2H), 6.24 (q, J=6.9 Hz, 1H), 4.40-4.26 (m, 1H), 3.90-3.68 (m, 4H), 3.63 (s, 3H), 2.55 (s, 3H), 1.72 (d, J=7.1 Hz, 3H). LCMS for C19H21ClN7O (M+H)+: m/z=398.1; Found: 398.1.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[C:9]([Cl:17])=[N:10][C:11]([CH:14]([F:16])[F:15])=[N:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.C(O)C>CC(C)=O>[Cl:17][C:9]1[C:8]([CH:6]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)[OH:7])=[CH:13][N:12]=[C:11]([CH:14]([F:15])[F:16])[N:10]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cnc(C(F)F)nc1Cl
Solvent: CC(C)=O
Solvent: CCO
Product: OC(c1ccc(Cl)cc1)c1cnc(C(F)F)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
12 g of 5-(4-chlorobenzoyl)-4-chlorodifluoromethylpyrimidine and 6 g of a t-butylamine borane complex were added to 100 ml of ethanol, and the resulting mixture was stirred at 0° C. for 2 hours. Then, 20 ml of acetone was added thereto, and the mixture was stirred at 0° C. for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform) to obtain 11.1 g of the desired product as a pale yellow viscous liquid. nD20.3 1.5563
Reaction SMILES: [CH:1](=[N:10][NH:11][C:12]([NH2:14])=[S:13])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[CH3:26])=O>>[CH3:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C:17]1[N:14]=[C:12]([NH:11]/[N:10]=[CH:1]/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[S:13][CH:16]=1
Reactant: NC(=S)NN=CC=Cc1ccccc1
Reactant: Cc1cc(O)ccc1C(=O)CBr
Product: Cc1cc(O)ccc1-c1csc(N/N=C/C=C/c2ccccc2)n1
Yield: 36 %

Procedure:
The compound is prepared according to the method described in example 1B from cinnamaldehyde thiosemicarbazone (0.28 mmoles) (Eur. J. Med. Chem. 25(7), 581-588, 1990) and from 2-bromo-4′-hydroxy-2′-methylacetophenone (0.28 mmoles). Yield 36%.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:31][C:30]3[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:34][CH:33]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (483 mg) in DMF (5 mL) was added potassium carbonate powder (744 mg) and 4-methylsulphonylbenzyl bromide (1.68 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40%-75% EtOAc/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:20](O)=[O:21])[N:16]=[CH:17]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:38])[C@@H:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[CH3:25][O:26][C:27](=[O:38])[C@@H:28]([NH:37][C:20]([C:15]1[N:16]=[CH:17][C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:9][C:8]1[CH:23]=[CH:24][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH:19]=2)=[O:21])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)ncc3c2)cc1
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cc2ccc(Oc3ccc(C(C)(C)C)cc3)cc2cn1
Yield: 75.2 %

Procedure:
500 mg (1.6 mmol) of 7-(4-tert-Butylphenoxy)-isoquinoline-3-carboxylic acid was reacted with 430 mg (1.8 mmol) of (2S)-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester as described in general procedure A. The crude product was purified by flash column chromatography on silica gel using 3:2 hexane/ethyl acetate as eluent, to afford 600 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][NH:22][C:23]1[C:27]([CH3:28])=[CH:26][N:25]([CH3:29])[N:24]=1>>[CH3:29][N:25]1[CH:26]=[C:27]([CH3:28])[C:23]([N:22]([CH3:21])[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])=[N:24]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CNc1nn(C)cc1C
Product: Cc1cn(C)nc1N(C)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 47b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 1 b) and N,1,4-trimethyl-1H-pyrazol-3-amine (which can be prepared from 3-formylamino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester CAN 114936-04-8 via reduction with lithium aluminum hydride in diethyl ether at ambient temperature) as starting materials and isolated as colorless oil. MS (EI): m/e=392.5 [MH+].
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:11][N:10]([CH:12]2[CH2:17][CH2:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]4[O:22][CH2:23][O:24][C:20]=4[CH:19]=3)=[CH:14][CH2:13]2)[CH2:9]1)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([C:15]3[CH2:16][CH2:17][CH:12]([N:10]4[CH2:11][CH:8]([NH2:7])[CH2:9]4)[CH2:13][CH:14]=3)=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
A solution of [1-(4-Benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-yl]-carbamic acid tert-butyl ester (as prepared in the previous step, 750 mg, 2.02 mmol) in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 2 hours. The solvent was removed under vacuum to give the title compound as colorless oil.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25](=O)[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:36]([NH:39][NH2:40])([CH3:38])[CH3:37].C(N(CC)CC)C>C(O)C>[Si:1]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:39]([CH:36]([CH3:38])[CH3:37])[N:40]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:26]=2)[CH2:20]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NN
Reactant: CCOC(=O)C(=O)CC(=O)C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C2C3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC32)n(C(C)C)n1
Reaction time: 16 h
Yield: 44.9 %

Procedure:
To a solution of ethyl 4-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-2,4-dioxobutanoate (0.40 kg, 84 mmol) in ethanol (500 mL) was added N-isopropylhydrazine hydrochloride (9.7 g, 84 mmol) at room temperature. After 16 h, triethylamine was added, and the resulting mixture was concentrated in vacuo. Purification of the residue by flash column chromatography (9% ethyl acetate in petroleum ether) afforded ethyl 5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-1-isopropyl-1H-pyrazole-3-carboxylate (19.5 g, 45%) as a colorless oil. LRMS: [M+H]+=517.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([F:11])([F:10])[F:9])[CH2:5][N:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[NH:18][C:19]([C:21]2[C:30]([NH:31]C(=O)OCC3C=CC=CC=3)=[CH:29][C:28]3[C:23](=[CH:24][C:25]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:26][CH:27]=3)[N:22]=2)=[O:20])[CH2:3]1>Br.CC(O)=O>[NH2:31][C:30]1[C:21]([C:19]([NH:18][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][C:12]=2[N:4]2[CH2:5][C@H:6]([C:8]([F:10])([F:11])[F:9])[CH2:7][C@H:2]([NH2:1])[CH2:3]2)=[O:20])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([N:42]1[CH2:43][CH2:44][O:45][CH2:46][CH2:47]1)[CH:24]=2
Reactant: N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Product: Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)Nc1cnccc1N1C[C@@H](N)C[C@@H](C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl {2-[({4-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-morpholin-4-ylquinolin-3-yl}carbamate (0.005 g, 0.008 mmol) in 2 mL of 4 M HBr in AcOH was stirred at room temperature for 2 h. The solution was then concentrated under reduced pressure and the residue was treated with 4.5 mL of MeOH and 0.5 mL of NH4OH solution. The resulting mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C25H29F3N7O2 [M+H]+: m/z=516.2. found: 516.3.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[C:12]([Cu])#[N:13].Cl>CN(C=O)C.O>[C:12]([CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])#[N:13]
Reactant: N#C[Cu]
Reactant: O=C(CCBr)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCC(=O)c1ccccc1
Temperature: 80 °C

Procedure:
Based on Kulkarni, N. R. Ayyangar, Tetrahedron, 1994, 50, 1243–1260. ]: A mixture of 3-bromopropiophenone (10.65 g, 50 mmol), CuCN (5.82 g, 65 mmol) in DMF (35 mL) was heated under reflux for 6 h. After cooling the mixture to ambient temperature FeCl3 (5 g) in H2O (30 mL)/HCl conc (10 mL) was added and heated to 80° C. for another 20 min. After cooling to room temperature and extraction with ether further purification occurred by destination under reduced pressure (bp.: 140° C., 10 torr). The ketone could be obtained as slightly yellow, low melting (42° C.) solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:34])=[C:5]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]>CCO.CCCCCC>[CH3:1][C:2]1[S:3][C:4]([CH3:34])=[C:5]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=2)[C:6]=1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3c(C)sc(C)c3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Solvent: CCO
Solvent: CCCCCC
Product: Cc1sc(C)c(C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
Methyl 4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoate from Example 16, Step 3 (172 mg, 0.353 mmol) was reacted under conditions similar to Example 1, Step 11. The crude solid was swished in 10:90 EtOH/hexane and the suspension was filtered. The resulting solid was rinsed with 10:90 EtOH/hexane, then hexane and dried to afford the desired product as a white solid. MS (−ESI): m/z 472 (M−1)−.
Reaction SMILES: [BH4-].[Na+].[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH3:20])[CH:11]=1)[CH2:5][C:6](OC)=[O:7]>CO>[NH2:3][CH:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH3:20])[CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: CCOc1cc(C(N)CC(=O)OC)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1cc(C(N)CCO)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a stirred solid of sodium borohydride (121 grams, 3.19 mol) at 0° C., was added methanol (50 mL). To this mixture at 0° C. was added a solution of methyl 3-amino-3-(3'-ethoxy-4'-methoxyphenyl)propionate (80.84 grams, 319.5 mmol) in methanol (1500 mL) over 1 hour. The mixture was stirred in that ice-water bath until the temperature of the reaction mixture stayed at 35° C. or lower for 30 minutes. (Early removal of the ice bath may result in a highly exothermic reaction). The water bath was then removed and the solution was refluxed for 16 hours. The solution was allowed to cool to room temperature. To the solution was added water (300 mL), followed by methylene chloride (250 mL) at 0° C. The resulting suspension was filtered. Half of the filtrate was removed in vacuo. The resulting solution was dissolved in methylene chloride (500 mL) and water (300 mL). The organic layer was separated. The aqueous layer was extracted with methylene chloride (3×500 mL). The combined organic layers were washed with brine (100 mL), and dried over magnesium sulfate. Removal of solvent gave an oil. The resulting oil was dried in vacuo to afford 3-amino-3-(3'-ethoxy-4'-methoxyphenyl)-1-propanol as a white solid (53 grams, 74% yield): 1H NMR (CDCl3)δ1.47 (t, J=6.8 Hz, 3H, CH3), 1.84-1.90 (m, 2H, CH2), 2.58 (br s, 3H, NH2, OH), 3.78 (t, J=5.5 Hz, 2H, OCH2), 3.86 (s, 3H, CH2), 4.04-4.15 (m, 3H, CH2, NCH), 6.84 (s, 3H, Ar); 13C NMR (CDCl3)δ14.74, 39.78, 55.84, 55.91, 61.86, 64.28, 110.55, 111.47, 117.58, 138.82, 148.27, 148.32; Anal. Calcd for C12H19 NO3 : C, 63.98; H, 8.50; N, 6.22. Found: C, 63.73; H, 8.44; N, 6.14.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:12]=[C:11]([NH2:13])[N:10]=[C:9]([NH2:14])[C:8]=2[NH2:15])=[CH:4][CH:3]=1.[N:16](OCCC(C)C)=O>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:15][N:16]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)CCON=O
Reactant: Cc1ccc(-c2nc(N)nc(N)c2N)o1
Solvent: C1COCCO1
Product: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
A solution of 6-(5-methyl-2-furyl)pyrimidine-2,4,5-triamine (5.8 g, 30.1 mmol) in dioxane (116 mL) was treated with isoamyl nitrite (4.1 mL, 30.5 mmol), heated at 80° C. for 3.5 h, cooled to room temperature and the resulting precipitate was filtered, washed with dioxane (10 mL) and heptane (2×15 mL) then triturated with heptane and filtered to give the title compound (4.7 g, 77%) as a sandy solid.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[N:13]=1.[OH-].[K+]>>[F:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([OH:19])[N:13]=1
Reactant: Cc1cccc(CBr)c1F
Reactant: Oc1cc(O)nc(S)n1
Agent: [K+]
Agent: [OH-]
Product: Cc1cccc(CSc2nc(O)cc(O)n2)c1F

Procedure:
The subtitle compound was prepared as a yellow solid by the method of Example 39 step i) using 2-fluoro-3-methylbenzyl bromide (7.0 g), 2-mercaptopyrimidine-4,6-diol (5.0 g) and potassium hydroxide (1.93 g). Yield: 8.36 g.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(=O)C.O>C1C=CC=CC=1.NCCC(O)=O>[C:1](/[C:3](=[CH:8]\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC#N
Agent: NCCC(=O)O
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)/C(C#N)=C/c1ccccc1
Yield: 91.3 %

Procedure:
A mixture containing 2.0 mL (22.7 mmoles) of methyl cyanoacetate, 2.38 g (22.4 mmoles) of benzaldehyde, 18 mg of β-alanine, and 1.00 mL of glacial acetic acid in 35 mL of benzene was heated at reflux for 2 hours with continuous azeotropic removal of water by means of a Dean-Stark trap. The product was isolated as described in the procedure of Example I, affording 3.83 g (91% yield) of crystalline cyanoester 2: mp 90°-91° C.