Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.C(OC([NH:15][CH2:16][C@H:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[ClH:27].[NH2:15][CH2:16][C@H:17]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 153.3 %

Procedure:
4M HCl/dioxane (5.49 ml, 22.0 mmol) was added to a solution of (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (0.329 g, 1.10 mmol) in 2:1 dioxane:DCM (10 mL). The reaction mixture was stirred at room temperature overnight (16 hours), after which it was concentrated to ⅓ volume. The resulting cloudy mixture was diluted with ether, and the mixture was concentrated again to ⅓ volume. The mixture was diluted again with ether (20 mL), and the solids were isolated by filtration through a medium frit funnel with nitrogen pressure, rinsed with ether (5×10 mL), dried under nitrogen pressure, and dried in vacuo to give (S)-3-amino-2-(4-chlorophenyl)propanoic acid hydrochloride (0.199 g, 76.8% yield) as a white powder. HPLC >99 area % pure. LC/MS (APCI+) m/z 200.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O>>[CH3:25][O:24][C:22]1[CH:23]=[C:15]2[C:16]([C:17](=[O:19])[N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:13])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:11](=[O:12])[NH:14]2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: COc1ccc(C(=O)O)c(N)c1
Product: COc1ccc2c(=O)n(S(=O)(=O)c3ccc(C)cc3)c(=O)[nH]c2c1
Yield: 50.8 %

Procedure:
269 mg (1.36 mmol) of p-toluenesulfonylisocyanate and 190 mg (1.20 mmol) of 2-amino-4-methoxybenzoic acid were treated in the same way as in Example 1 to obtain 211 mg of the above-identified compound (yield 53.5%). Properties: colorless crystal, Melting point: 228°-231° C., PMR (δppm, DMSO-d6):2.43 (3H,s), 3.79 (3H,s), 7.07 (1H,d), 7.29 (2H,br), 7.45-7.54 (2H,m), 8.04 (2H,d), 11.37 (1H,s).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:36])=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=3)[CH:27]=2)OC1>>[F:36][C:25]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]3=[N:4][CH:3]=2)=[CH:27][C:26]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cccc(C#N)c3)c2)OC1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: N#Cc1cccc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2′-fluorobiphenyl-3-carbonitrile as described in Example 65 to give 2′-fluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-3-carbonitrile as a yellow solid: δH (360 MHz, CDCl3) 7.28 (1H, d, J 7), 7.40-7.46 (1H, m), 7.55-7.64 (3H, m), 7.72-7.75 (1H, m), 7.83 (1H, dd, J 7 and 1), 7.89 (1H, d, J 1), 8.11 (1H, s), 8.75 (1H, d, J 7); m/z (ES+) 383 (M++H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([SH:33])[NH:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]=[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)[NH:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1c[nH]c(S)n1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Product: CCOC(=O)c1c[nH]c(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)n1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and ethyl-2-mercapto-1H-imidazole-4-carboxylate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[H-].[Na+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])[O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (20.7 g, 120.19 mmol) and 2,4-difluoronitrobenzene (19.125 g, 120.19 mmol) in DMF at 5° C. was added NaH (5.05 g, 126.2 mmol) in one portion, resulting in a slow exotherm to 10° C. The reaction was stirred at 5° C. for 1 hour then allowed to warm to ambient temperature and stirred for 24 hr. The reaction was cooled to 0° C. and quenched with water (˜400 mL). The mixture was extracted with EtOAc (3×˜150 mL), the organic layers combined, washed with brine (2×˜100 mL), dried (MgSO4), filtered and evaporated to an orange oil (36 g). The crude residue was purified by preparative HPLC (silica, 4:1 ethyl acetate:isohexane) to give the title compound (4.5 g, 12%) as a pale orange oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9](Br)[N:10]2[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CO.C(COC)OC>[NH2:5][C:6]1[N:14]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[N:12]=[C:11]2[C:7]=1[N:8]=[C:9]([O:2][CH3:1])[N:10]2[CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1
Reactant: C[O-]
Reactant: COCCOc1nc(N)c2nc(Br)n(Cc3ccc(C#N)cc3)c2n1
Agent: [Na+]
Agent: [Na]
Solvent: COCCOC
Solvent: CO
Product: COCCOc1nc(N)c2nc(OC)n(Cc3ccc(C#N)cc3)c2n1
Temperature: 100 °C

Procedure:
Sodium methoxide is generated by reaction of sodium metal (81 mg) in dry methanol (30 mL). The product of example 4 (700 mg) is dissolved in dry dimethoxyethane and the temperature raised to 100° C. After overnight reaction, the mixture is concentrated in vacuo and the residue is chromatographed on silica using 5% methanol in dichloromethane. Yield 120 mg. NMR is consistent with structure assignment.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: N#CCCN1C[C@H](O)C[C@@H]1CO
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@H](O)C[C@@H]3CO)cc12

Procedure:
In the same manner as in Example 1b (e) and using 3-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile (total amount) and N,N-diethyl-2,3-dimethylbenzamide (4.1 g), 3-{2-[(2R,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one (0.47 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][N:13]([C:28]([N:30]3[CH2:35][CH2:34][S:33][CH2:32][CH2:31]3)=[O:29])[CH2:12]2)[O:8][N:7]=1.ClC1C=CC=C(C(OO)=[O:44])C=1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([F:25])([F:27])[F:26])=[CH:21][CH:22]=3)[CH2:14][N:13]([C:28]([N:30]3[CH2:35][CH2:34][S:33](=[O:44])[CH2:32][CH2:31]3)=[O:29])[CH2:12]2)[O:8][N:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Product: COCCOc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1

Procedure:
46.7 mg (0.091 mmol) of the compound from Example 70 were reacted according to General Method 2 with 28.2 mg (0.082 mmol) of meta-chloroperbenzoic acid. Yield: 52.8 mg (100% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[N+:19]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33])([O-:21])=[O:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH:17][S:32]([C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=1[N+:19]([O-:21])=[O:20])(=[O:33])=[O:34])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2-nitro-4-trifluromethylbenzenesulfonylchloride, the title com-pound was obtained in a similar yield:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([NH:31][CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]>ClCCl>[CH:13]([O:16][C:17]([N:19]1[C:28]2[C:23](=[N:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=2)[C@H:22]([N:31]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:21][C@@H:20]1[CH3:47])=[O:18])([CH3:15])[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C)N(C(=O)OC(C)C)c2ccc(OC)nc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
Add ethyl chloroformate (0.118 mL, 1.240 mmol), followed by pyridine (0.205 mL, 2.52 mmol), to a solution of (+/−)-cis-4-(3,5-bis-trifluoromethyl-benzylamino)-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.210 g, 0.415 mmol) in dichloromeihane (3 mL). After stirring at room temperature for 12 h remove the solvent in vacuo. Purify using silica gel chromatography, eluting with ethyl acetate/hexane (gradient eluent, 0-30% ethyl acetate in hexane) to afford the title compound (0.218 g, 92%): MS (ES+): 578 (M+H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[C:8]2([Cl:17])[Cl:16])(=[O:4])=[O:3].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[CH2:18]([NH:25][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[C:9](=[O:15])[C:8]2([Cl:17])[Cl:16])(=[O:4])=[O:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: CN1C(=O)C(Cl)(Cl)c2cc(S(=O)(=O)Cl)ccc21
Agent: Cl
Solvent: ClCCl
Product: CN1C(=O)C(Cl)(Cl)c2cc(S(=O)(=O)NCc3ccccc3)ccc21
Reaction time: 8 h

Procedure:
To a solution of 5-chlorosulfonyl-N-methyl-3,3-dichloro-2-oxindole (120 mg, 382 umol) in methylene chloride (5 mL) was added benzyl amine (50 uL, 458 umol) dropwise. After stirring overnight, 3 N hydrochloric acid was added along with an additional volume of methylene chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered, and silica gel flash chromatography (35 to 55% ethyl acetate/hexanes) yielded the title compound. ES (−) MS m/e=383 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5](=[O:17])[N:4]2[CH2:18][CH2:19][S:20][C:3]=12.[CH:21]1([S:24](Cl)(=[O:26])=[O:25])[CH2:23][CH2:22]1>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:24]([CH:21]2[CH2:23][CH2:22]2)(=[O:26])=[O:25])=[C:3]2[S:20][CH2:19][CH2:18][N:4]2[C:5](=[O:17])[CH:6]=1
Reactant: Nc1c(Nc2ccc(I)cc2F)cc(=O)n2c1SCC2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: O=c1cc(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n1CCS2
Yield: 19.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 19A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (0.08 g, 0.199 mmol) in pyridine (1 mL) was reacted with cyclopropylsulfonyl chloride (33 mg, 0.238 mmol) to afford the crude product. Purification by preparative HPLC afforded 20 mg of the product (20% yield).
Reaction SMILES: [O:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:13]([Cl:19])=[C:14](F)[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[C:13]([Cl:19])=[C:14]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][O:1][C:9]2=3)[CH:15]=[CH:16][CH:17]=1
Reactant: Fc1cccc(Br)c1Cl
Reactant: OC1CNCc2ccoc21
Product: Clc1c(Br)cccc1OC1CNCc2ccoc21

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 33) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[OH:26][C:25]1[C:20]([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ncccc1O
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: O=C(Nc1ncccc1O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-aminopyridin-3-ol as the starting materials.
Reaction SMILES: C([O:4][C@H:5]([CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([F:29])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH3:31])(=O)C.N>CO>[OH:4][C@H:5]([CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:18][C:19]3[C:20]([F:29])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:30][CH3:31]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Agent: N
Solvent: CO
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@H](O)CN1CCCC1
Yield: 74.6 %

Procedure:
A solution of (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (570 mg, 1.12 mmol) in methanol saturated with ammonia (7 ml) was stirred overnight at ambient temperature. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol containing ammonia (approximately 3N) to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (390 mg; 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]#[N:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:40]([Sn](C)(C)C)=[N+:41]=[N-:42].C1(C)C=CC=CC=1.Cl>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[C:23]([C:34]4[NH:42][N:41]=[N:40][N:35]=4)[CH:22]=3)[CH:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C#N)c1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn[nH]2)c1
Temperature: 110 °C
Yield: 99.9 %

Procedure:
A mixture of 4-[6-butyl-5-(3-cyano-4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 67, 0.944 mmol, 505 mg), azidotrimethyltin (3.78 mmol, 802 mg, 97%) and toluene (9 mL) was heated at 110° C. for 48 h. More azidotrimethyltin (0.95 mmol, 201 mg, 97%) was added and the reaction mixture was heated at 110° C. for another 24 h. The reaction mixture was stirred with aq. 0.41 N HCl (11.5 mL), diluted with water (30 mL) and extracted with DCM (2×40 mL). The combined DCM extracts were dried over sodium sulfate. Purification by column chromatography on silica gel using 0-7.5% MeOH in DCM gave 4-{6-butyl-5-[4-cyclohexyloxy-3-(1H-tetrazol-5-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester as light brown solid (545 mg).
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.I[CH3:25]>>[CH3:25][O:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1
Reactant: CI
Reactant: CSc1ccc(C2(O)CCC(C#N)(c3ccccc3)CC2)cc1
Product: COC1(c2ccc(SC)cc2)CCC(C#N)(c2ccccc2)CC1

Procedure:
1.50 g of 4-hydroxy-4-(4-methylsulfanylphenyl)-1-phenylcyclohexanecarbonitrile were reacted with iodomethane according to the process described in Example 40. 1.19 g of the title compound were obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][NH:18][C:17]1=[O:21])(=[O:11])=[O:10]
Reactant: NCCN1CCNC1=O
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1NCCN1CCNS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
A solution of 0.5 g (2.04 mmol) of 2,3-dichlorobenzenesulphonyl chloride, 0.26 g (2.04 mmol) of 1-(2-aminoethyl)-2-imidazolidone and 1 ml (7.18 mmol) of triethylamine in 10 ml of tetrahydrofuran was stirred at room temperature overnight. The reaction mixture was then washed with 1 N HCl and saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. The product obtained in this manner was reacted further without additional purification.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH:17]1([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:19][CH2:18]1>>[CH:17]1([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([C:2]3[CH:16]=[CH:15][C:5]4[C:6]([CH:9]5[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]5)=[N:7][O:8][C:4]=4[CH:3]=3)[CH:23]=2)[CH2:18][CH2:19]1
Reactant: Brc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3CCNCC3)noc2c1

Procedure:
Example 1 was prepared by General Method A using 6-bromo-3-piperidin-4-yl-1,2-benzisoxazole and Intermediate 5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:8][N:9]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][O:2][C:3](=[O:17])[NH:4][C:5]1[S:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:18]3[CH2:21][CH:20]([NH:22][C:23](=[O:24])[CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=4)[CH2:19]3)[CH2:12][CH2:11]2)=[CH:8][N:9]=1
Reactant: COC(=O)Nc1ncc(C2CCC(=O)CC2)s1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COC(=O)Nc1ncc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from the reductive amination of [5-(4-oxo-cyclohexyl)-thiazol-2-yl]-carbamic acid methyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14].O.[C:17]([OH:21])(=[O:20])[CH:18]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])/[CH:14]=[CH:18]/[C:17]([OH:21])=[O:20]
Reactant: O=CC(=O)O
Reactant: COc1ccc(OC)c(/C=C/C(C)=O)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OC)c(/C=C/C(=O)/C=C/C(=O)O)c1

Procedure:
A solution of 19 g (92 mmol) of (E)-4-(2,5-dimethoxyphenyl)but-3-en-2-one and 8.4 g (92 mmol) of glyoxylic acid monohydrate in 23.4 ml of acetic acid was boiled at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/ethyl acetate yielded (E,E)-6-(2,5-dimethoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 145°-146°.
Reaction SMILES: O[Li].O.[CH3:4][C:5]1[C:6]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([O:29]C)=[O:28])=[N:7][C:8]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:9][CH:10]=1>O.C1COCC1>[CH3:4][C:5]1[C:6]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][C:27]([OH:29])=[O:28])=[N:7][C:8]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)=[N:9][CH:10]=1
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(Nc2cnn(C)c2)nc1CCc1ccccc1CC(=O)O
Temperature: 40 °C

Procedure:
LiOH.H2O (0.534 g, 12.7 mmol) was added to a solution of methyl 2-(2-(2-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)ethyl)phenyl)acetate (A116) (0.093 g, 0.25 mmol) in H2O (1 mL) and THF (10 mL) and the resulting mixture heated at 40° C. for 18 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (100 mL), washed with aqueous 2 M HCl (50 mL), water (100 mL), brine (50 mL) and dried over MgSO4. The combined aqueous layers were additionally extracted with chloroform/isopropanol (4:1, 2×50 mL). The organic extracts were then combined, dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound A117 as a yellow solid (0.067 g, 75%); LCMS-A: rt 4.718 min; m/z 352 [M+H]+.
Reaction SMILES: C(O[CH2:4][CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8])C.[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:4][CH:5]=[C:6]([C:9]#[N:10])[C:7]#[N:8]
Reactant: CN
Reactant: CCOCC=C(C#N)C#N
Product: CNCC=C(C#N)C#N

Procedure:
[(Methylamino)ethylidene)methane-1,1-dicarbonitrile was synthesized in the same manner using (ethoxyethylidene)methane-1,1-dicarbonitrile and methylamine. The NMR data for this compound are shown below.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH2:3][CH2:2]1
Reactant: OCc1csc(N2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1csc(N2CCOCC2)n1

Procedure:
The reaction described in Preparation 44 was repeated but using 2.4 g of 2-morpholinothiazol-4-ylmethanol, 5.7 g of sulfur trioxide pyridine complex. 3.6 g of triethylamine and 30 ml of dimethyl sulfoxide, giving the title compound as pale yellow needles.