Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of 3-benzyloxyphenylacetonitrile (11.50 g, 51.50 mmol) in 100 mL of THF at 0° C. was treated with LiAlH4 (3.90 g, 103 mmol) in several portions over 20 minutes. The reaction mixture was warmed to room temperature and stirred for 30 minutes then it was heated at reflux for 6 h. The suspension was cooled to room temperature and quenched by the slow addition of Na2SO4.10H2O (25 g). The resulting mixture was diluted with 200 mL of CH2Cl2. The organic layer was separated and the remaining salt was rinsed with additional CH2Cl2 (2×50 mL). The combined organic layers were dried over MgSO4, concentrated, and purified by column chromatography (SiO2, hexanes/ethyl acetate, 2:1) to provide the title compound (5.85 g, 51% yield): ES-MS (m/z) 228 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CCCCCCCCCCCCCN1CCC(CN)CC1
Product: CCCCCCCCCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 44.8 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-tridecylpiperidine (0.596 g, 2.0 mmol) of according to procedure used for Example 2 to give 0.240 g of the title compound as a white solid (mp-70-72° C., Et2O).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+].[I:14]I.S([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[I:14][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: N#Cc1ccc2cn[nH]c2c1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc2c(I)n[nH]c2c1
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a suspension of 1H-indazole-6-carbonitrile (4.5 g, 31.4 mmol) and KOH (5.3 g, 94.2 mmol) in DMSO (50 mL), was added iodine (15.9 g, 62.8 mmol) portion-wise over 10 minutes at 0° C. under ice-water bath. The final mixture was stirred for additional 2 hours at room temperature. The mixture was added slowly into saturated sodium sulfite (300 mL), the formed solid was stirred for 10 minutes, filtered, washed with saturated sodium sulfite (2×50 mL), water (2×20 mL) and dried, giving 3-iodo-1H-indazole-6-carbonitrile light as yellow solid (8.1 g, yield 95.6%). MS: (M+H)+=411; 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.33 (s, 1H), 7.80 (s, 1H), 6.20 (s, 2H), 1.52 (s, 9H), 1.15 (s, 9H).
Reaction SMILES: C([O:8][C:9](=[O:41])[C@@H:10]([NH:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=1)(=[O:33])=[O:32])=[O:24])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].C(O)C>[F:40][C:36]1[CH:35]=[C:34]([S:31]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]2[C:23]([NH:22][C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[C:9]([OH:41])=[O:8])=[O:24])(=[O:32])=[O:33])[CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)Oc1ccc(C[C@H](NC(=O)C2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)O)cc1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of (S)-2-{[(S)1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-isopropoxy-phenyl)-propionic acid benzyl ester (0.59 g, 1.00 mmol), ethanol (20 mL) and 10% Pd on carbon (108 mg, 0.1 mmol) was hydrogenated at 30 psi for 2 h. The catalyst was filtered through Celite®. The filtrate was concentrated to afford 410 mg (83.0%) of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][C:19](=O)C)=[C:14]([F:22])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].CI>CN1CCCC1=O>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[C:14]([F:22])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(SC(C)=O)c(F)c2)C(=O)O1
Solvent: CI
Solvent: CN1CCCC1=O
Product: CSc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Reaction time: 8 h

Procedure:
Prepared according to Method A of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli dine-2-ones from BAL resin immobilized 5-(S)-acetamidomethyl-3-[4′-actylthio-3′-fluorophenyl]oxazoli-dine-2-one with methyl iodide (0.05 mL, 0.81 mmol) in N-methylpyrrolidine-2one (1 mL). The synthesis was performed at r.t. overnight, and the crude cleaved product purified by TLC (eluent: 10% methanol in dichloromethane). Yield 6.3 mg (52%). MS: 299 [M+H]+. 1H NMR.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2[C:6](=[N:7][C:8]3[C:9]=2[CH2:11][CH:12]=[CH:13][C:14]=3[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]1([CH3:23])[C:10]2[C:6](=[N:7][C:8]3[C:9]=2[CH:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:13][C:14]=3[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CCCCCCCCBr
Reactant: CC1(C)CCCC2=NC3=C(OCc4ccccc4)C=CCC3=C21
Product: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCC(C)(C)C3=C21
Yield: 50.3 %

Procedure:
Using the procedure of Example 9, the alkylation of 7.7 g of 1,2,3,4-tetrahydro-1,1-dimethyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 58 was reacted with 5.48 g of 1-bromooctane to produce 5.3 g (50.5%) of 1,2,3,4-tetrahydro-1,1-dimethyl-6-phenylmethoxy-9-octyl-9H-dibenzo-[b,d]pyrrole as an orange oil after chromatographic purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH:30]([NH:33][C@@H:34]([CH3:48])[CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1)([CH3:32])[CH3:31]>>[CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([N:33]([CH:30]([CH3:32])[CH3:31])[C@@H:34]([CH3:48])[CH2:35][O:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=4)=[O:22])=[CH:24][CH:25]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2]
Reactant: CC(C)N[C@@H](C)COCc1ccc(C(F)(F)F)cc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)[C@@H](C)COCc3ccc(C(F)(F)F)cc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N-isopropyl-N—[(S)-1-methyl-2-(4-trifluoromethyl-benzyloxy)-ethyl]-amine as described for example 1.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]([CH3:27])[CH3:26])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[OH:28][C:29]1([CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[OH:28][C:29]1([CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][C:41]3[C:46]([CH:47]=2)=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:34][CH2:33][N:32]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([C@H:14]([CH:25]([CH3:27])[CH3:26])[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:31][CH2:30]1
Reactant: CC(C)[C@H](C(=O)OCc1ccccc1)N1C[C@H](c2ccccc2)[C@@H](C=O)C1
Reactant: OC1(CCCc2cnc3ccccc3c2)CCNCC1
Product: CC(C)[C@H](C(=O)OCc1ccccc1)N1C[C@H](CN2CCC(O)(CCCc3cnc4ccccc4c3)CC2)[C@@H](c2ccccc2)C1
Yield: 78.3 %

Procedure:
The title compound was prepared from 24 mg (0.067 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-methylbutanoic acid, benzyl ester (from EXAMPLE 5, Step D) and 22.5 mg (0.073 mmol) of 4-hydroxy-4-(3-(quinolin-3-yl)propyl)piperidine.HCl from EXAMPLE 6, Step A using a procedure analogous to that described in EXAMPLE 1, Step J to provide 32.5 mg (75%) of the title compound: RF: 0.21 (19:1 v/v CH2Cl2/MeOH); 1H NMR (300 MHz) δ 0.88 (d, J=6.7,33H), 1.01 (d, J=6.7, 3H), 1.42-3.22 (m, 24H), 5.16 (ABq, 2H), 7.15-7.41 (m, 10H), 7.49-7.54 (m, 1H), 7.62-7.68 (m, 1H), 7.75 (d, J=8.0, 1H), 7.91 (s, 1H), 8.06 (d, J=8.2, 1H), 8.75 (d, J=2.1, 1H).
Reaction SMILES: O.[NH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[OH:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[OH:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:3]2[NH:2][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c(O)cccc12
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1cccc2c(O)cccc12
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Into a 500 ml round bottom flask (fitted with a magnetic stirrer), a 50:50 mixture of water:ethanol was combined with 5-amino-1-naphthol (20 g, 125 mmole) until the solid was completely dissolved. The solution was warmed to boiling and to it was added acetic anhydride (14 g) and the resulting solution was stirred for 1 hour. Upon cooling, crystals of N-(5-hydroxy1-napthyl)acetamide (21 g, 84% yield) formed.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:28])([CH3:27])[C:25]#[N:26])=[C:20]([F:29])[CH:19]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([C:25]#[N:26])([CH3:28])[CH3:27])=[C:20]([F:29])[CH:19]=3)=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C#N)c1ccc(CN)cc1F
Reactant: O=C(O)Cn1cnc2cccc(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3cccc(Cl)c32)cc1F

Procedure:
2-(7-Chloro-1H-benzimidazol-1-yl)-N-[4-(1-cyano-1-methylethyl)-3-fluorobenzyl]acetamide is synthesized according to example 14 with (7-chloro-1H-benzimidazol-1-yl)acetic acid (150 mg, 0.712 mmol) prepared according to scheme 1, and 2-[4-(aminomethyl)-2-fluorophenyl]-2-methylpropanenitrile hydrochloride (196 mg, 0.855 mmol) prepared according to scheme 8, Et3N (238 μL, 1.71 mmol) and HATU (325 mg, 0.855 mmol) in DMF (3.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5%) 21.2×50 mm, Mobile phase: A=water (0.075% TFA) B=MeCN (0.075% TFA). Yield=14 mg as TFA salt, 0.035 mmol, 5%); 1H NMR (400 MHz, DMSO-D6) δ ppm 1.67 (s, 6H), 4.30 (d, J=5.86 Hz, 2H), 5.24 (s, 2H), 7.10-7.22 (m, 3H), 7.23-7.28 (m, 1H), 7.38 (t, J=8.40 Hz, 1H), 7.62 (d, J=7.81 Hz, 1H), 8.31 (s, 1H), 8.81 (s, 1H). MS [M+H], calcd: 385.1, found: 385.0.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])=[CH:7][CH:8]=1.[OH-].[Na+]>>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[N:5][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:13])=[O:12])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cn1
Yield: 72.7 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 3-trifluoromethylpyridine-6-ylbenzoate (791 mg) and aqueous sodium hydroxide solution (1N, 5.60 ml) and the reaction mixture was treated to afford the title compound (546 mg) which includes some impurity and was used in example 106 without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.N1CCCC1.I[CH2:20][C:21]([NH2:23])=[O:22]>C1(C)C=CC=CC=1.O1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[C:4]2[CH2:5][CH2:6][C:7]3[NH:23][C:21](=[O:22])[CH2:20][C:8]=3[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc2c1CCC(=O)C2
Reactant: NC(=O)CI
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1CCC1=C2CC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
439 g (2.49 mol) of 5-methoxy-2-tetralone and 227 ml (3.67 mol) of pyrrolidine were dissolved in 3 l of toluene. After the addition of 16.4 g (0.09 mol) of p-toluenesulfonic acid monohydrate the mixture was boiled for 4 hours, whereby the resulting water was removed continuously using a water separator. Thereupon, the toluene was distilled off in a vacuum. The residue was dissolved in 1 l of tetrahydrofuran, whereupon a solution of 500 g (2.70 mol) of iodoacetamide in 2.5 l of tetrahydrofuran was added dropwise at room temperature. The mixture was boiled at reflux for 30 minutes, then cooled to room temperature and stirred for a further 12 hours. The solid was filtered off and washed with tetrahydrofuran. There were obtained 475 g (89%) of 1,3,4,5-tetrahydro-6-methoxy-2H-benzo[e]indol-2-one as white crystals with m.p. 220°-222°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH2:22]([O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH:14]=[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(OCc3ccccc3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
4-(3-Benzyloxy-benzylidene)-piperidine-1-carboxylic acid tert-butyl ester (534 mg, 1.4 mmol) from Step 2 was dissolved in CH2Cl2 (5 mL) and treated with trifluoroacetic acid (1.05 mL, 14.1 mmol). After 2 hours, the solution was concentrated to provide the title compound which was used without further purification (550 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]2[N:12]=[C:13]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:14]3[N:20]=[C:19]([CH2:21][CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl>O1CCOCC1>[F:1][C:2]1[C:3]([C:11]2[N:12]=[C:13]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[C:14]3[N:20]=[C:19]([CH2:21][CH:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)[CH:18]=[CH:17][C:15]=3[N:16]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1

Procedure:
Crude tert-butyl 4-((2-(5-fluoro-1H-indol-4-yl)-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidine-1-carboxylate 137 was reacted with 4N HCl in dioxane and purified by reverse phase HPLC to afford 16 mg of 139. MS (Q1) 447.2 (M)+
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:8]1([Mg]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: ON1CCCCC1
Reactant: Cl[Mg]C1CCCCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCCCC1C1CCCCC1
Reaction time: 1 h
Yield: 26.6 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxy-piperidine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclohexylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 40% diethyl ether in hexanes to give the title compound (0.241 g, 27%) as a white crystalline solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]([F:20])([F:19])[CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[ClH:21]>C(#N)C>[ClH:21].[NH2:8][C@@H:9]([CH2:13][C:14]([F:19])([F:20])[CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(F)(F)CC1CC1)C(=O)O
Agent: Cl
Solvent: CC#N
Product: N[C@@H](CC(F)(F)CC1CC1)C(=O)O
Yield: 86.7 %

Procedure:
(5)-2-(tert-butoxycarbonylamino)-5-cyclopropyl-4,4-difluoropentanoic acid (75 g, 0.256 mol, 1 eq), prepared as in Example 10, was added to a 2 L round bottomed flask fitted with a mechanical stirrer, nitrogen inlet and thermometer. A mixture of hydrochloric acid (13.7 g, 0.375 mol, 1.5 eq) and acetonitrile (750 mL) and was added. White solids precipitated out during the reaction. After 2 hours the solids were filtered, washed with acetonitrile and dried in a vacuum oven at 30° C. for 24 hours to provide (S)-2-amino-5-cyclopropyl-4,4-difluoropentanoic acid hydrochloride (51 g, 87% yield). 1H NMR confirmed the desired structure.
Reaction SMILES: C(S([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]2[CH:18]=[C:19]([C:22]3[C:23]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[N:24][N:25]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[CH:20]=[CH:21][C:8]=2[N:7]=1)(=O)=O)C.[H-].[Na+].O.[C:56](OCC)(=[O:58])C>O1CCCC1.CO>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:9]3[CH:18]=[C:19]([C:22]4[C:23]([C:46]5[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=5)=[N:24][N:25]([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:26]=4)[CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[O:58][CH3:56])=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: CCS(=O)(=O)c1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1

Procedure:
50 mg 2-(ethylsulfonyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole obtained in Example 138 was dissolved in 0.5 mL tetrahydrofuran and 3 mL methanol, then 28 mg sodium hydride was added thereto, and the mixture was heated for 3 hours under reflux under nitrogen atmosphere. After the reaction mixture was cooled, water and ethyl acetate were added thereto, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-2-methoxy-1H-benzo[d]imidazole. This product was subjected to deprotection of the trityl group in the same manner as in Example 84 and then purified by NAM silica gel chromatography (ethyl acetate/methanol), to give 18 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.C1C(=O)N([I:24])C(=O)C1>C(Cl)Cl.CO>[I:24][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][C:6]=1[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1
Reactant: Cc1cc(C)cc(-c2cc(C)nc(N)n2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2nc(N)nc(C)c2I)c1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 3.2 g (11 mmol) 4-methyl-6-(3,5-dimethyl-phenyl)-pyrimidin-2-ylamine and 2.5 g (11 mmol) NIS. Yield after chromatography on silica gel with DCM/MeOH: 1.1 g (31%).
Reaction SMILES: Cl[C:2]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[N:7]=[C:6]([C:16]([O:18][CH3:19])=[O:17])[CH:5]=1)=[O:3].[NH3:20]>O1CCCC1>[NH2:20][C:2]([C@@H:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:15])=[CH:11][C:12]=2[Cl:14])[NH:7][C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1)=[O:3]
Reactant: COC(=O)c1cc(C(=O)Cl)c2c(Cl)cc(Cl)cc2n1
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](C(N)=O)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorocarbonyl-5,7-dichloro-2-methoxycarbonylquinoline (1.5 g) was dissolved in dry tetrahydrofuran (20 ml) at 0° C. and an ice-cool solution of tetrahydrofuran (150 ml), presaturated with ammonia gas, was added in one portion. After stirring at room temperature for 30 minutes the white solid which precipitated was collected by filtration and dried (1.4 g). A portion of this solid (1 g) was suspended in glacial acetic acid (20 ml) and sodium cyanoborohydride (1.3 g) was added in portions. When the addition was complete the reaction mixture was heated at 50° C. for 2 h, cooled and stirred at room temperature for 14 h. The solution was diluted with dichloromethane (to a volume of 100 ml) and ice cold 50% sodium hydroxide solution added cautiously until a pH of 14 was attained. The organic layer was separated and the aqueous layer was re-extracted with dichloromethane (2×100 ml). The combined organic fractions were washed with brine (1×150 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by chromatrography on silica gel with 2% methanol in dichloromethane as eluent to give, as the less polar isomer, trans-4-aminocarbonyl-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.15 g, m.p. 217°- 229° C. [recrystallised from methanol]); δ (360 MHz, DMSO) 1.83 (1H, m, CHACHBHCCHD), 2.32 (1H, dm, J=13.2 Hz, CHACHBHCCHD), 3.72 (3H, s, CH3), 3.78 (1H, dd, J=5.8 and 2.0 Hz, CHACHBHCCHD), 4.01 (1H, dd, J=12.2 and 2.1 Hz, CHACHBHCCHD), 6.63 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.66 (1H, br, s, NH), 6.78 (1H, d, J=2.1 Hz, 6-H or 8-H), 7.02 (1H, br, s, NH), 7.51 (1H, br, s, NH); m/e 302 (M+), 198 (100%, M-H, CONH2 and CO2CH 3); Found: C, 47.46; H, 3.95; N, 9.18 C12H12Cl2N2O3 requires C, 47.55; H, 3.99; N, 9.24%; and as the more polar isomer, cis-4-aminocarbonyl-5,7-dichloro-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline (0.14 g, m.p. 203°-204° C.); δ (360 MHz, DMSO), 2.05 (1H, m, CHACHBHCCHD), 2.52 (1H, m, CHACHBHCCHD), 3.54 (3H, s, CH3), 3.71 (1H, dd, J=7.2 and 3.4 Hz, CHACHBHCCHD), 4.11 (1H, dd, J=5.2 and 3.2 Hz, CHACHBHCCHD), 6.61 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.70 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.84 (2H, br, s, CONH2), 7.20 (1H, br, s, NH); m/e (CI+) 303 (M+1); Found: C, 47.38; H, 3.98; N, 9.14. C12H12Cl2N2O3 requires C, 47.55; H, 3.99; N, 9.24%.