Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:16]([N:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:7][CH2:8]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
tert-Butyl 4-(methylamino)piperidine-1-carboxylate (3.0 g, 14.019 mmol, 1.0 eq.) was dissolved in DCM (30 ml); benzaldehyde (1.7 ml, 16.823 mmol, 1.2 eq.) was added and the mixture was stirred for 1 hour at RT. NaBH(OAc)3 (4.81 g, 28.038 mmol, 3.0 eq.) was then added at 0° C. and the reaction mixture was stirred for 14 hours at RT. After monitoring by TLC, DCM (300 ml) was added to the reaction and washing was carried out in succession with sodium hydrogen carbonate solution (100 ml), water (100 ml) and sat. NaCl solution (100 ml). The organic phase was dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 1% MeOH in DCM). Yield: 28% (1.2 g, 3.947 mmol)
Reaction SMILES: C(OC([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>CCO.O>[CH:18]1[C:11]2[S:10][C:9]3[CH2:8][CH2:7][NH:6][CH2:15][CH2:14][C:13]=3[C:12]=2[NH:16][CH:17]=1
Reactant: CCOC(=O)N1CCc2sc3cc[nH]c3c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1cc2sc3c(c2[nH]1)CCNCC3
Temperature: 100 °C

Procedure:
To a stirred solution of the product from step (g) (0.049 g, 0.19 mmol) in EtOH (2 ml) was added 40% aqueous KOH (2 ml). The reaction mixture was heated to 100° C. until LCMS indicated no starting material present (usually 16-32 hours). The reaction mixture was cooled to RT, diluted with water (30 ml) and extracted with DCM (3×). The combined DCM extracts were dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by preparative LCMS gave the title compound as a tan solid. 1H NMR (CDCl3) δ 8.05 (bs, 1H), 6.95-6.90 (m, 1 H), 6.41-6.36 (m, 1H), 3.10-3.02 (m, 4H), 3.00-2.94 (m, 2 H), 2.92-2.82 (m, 2 H); MS: ESI (positive): 193 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]([CH3:8])[C:3]1=[S:9].CNCC#N.CN=C=S.[CH3:19][N:20]=[C:21]=[O:22]>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:6][CH:5]([NH:7][C:21]([NH:20][CH3:19])=[O:22])[N:4]([CH3:8])[C:3]1=[S:9]
Reactant: Cn1cc(N)n(C)c1=S
Reactant: CN=C=O
Agent: CN=C=S
Agent: CNCC#N
Solvent: c1ccncc1
Product: CNC(=O)NC1CN(C)C(=S)N1C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of 3.22 grams (0.0225 mol) of 1,3-dimethyl-4-amino-4-imidazoline-2-thione (prepared from methylaminoacetonitrile and methyl isothiocyanate by the method of T. Kinoshita et al, Bull. Chem. Soc. Japan., 53, 442 (1980)) in 12 mL of pyridine under an atmosphere of nitrogen was added with stirring 2.61 grams (0.0457 mol) of methyl isocyanate. The mixture became exothermic. Stirring was continued overnight whereupon a solid precipitate formed in the reaction mixture. The latter was collected by filtration and washed with isopropyl alcohol to obtain 2.11 grams of 1,3-dimethyl-4-(methylaminocarbonylamino)-imidazoline-2-thione, m.p. 200°-201° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)[CH:26]=1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH2:35][CH:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][NH:23][CH3:22])[CH:26]=3)[CH2:32]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CNCc1cccc(C2CCNC2)c1
Product: CNCc1cccc(C2CCN(c3c(F)c(N)c4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)c1
Yield: 55 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.52 g, 1.7 mmol) and N-methyl-3-(3-pyrrolidinyl)benzenemethanamine, a procedure analogous to that given in Example 1 provided the title compound (0.44 g, 55%) as a yellow solid, mp >270° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][C@H:11]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C@@H:11]([CH3:12])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)=CCC[C@H](C)CCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCC[C@H](C)CCOc1ccc(Br)cc1
Yield: 590.9 %

Procedure:
A mixture of 4-bromophenol (34.6 g, 0.20 mol), (S)-(+)-citronellyl bromide (50 g, 0.023 mol) and potassium carbonate (45 g, 0.33 mol) in butanone (500 cm3) was heated under reflux overnight. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure. The crude product was purified by fractional distillation to yield 42.3 g (68.2%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:13](=[O:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[C@@H:13]([OH:16])[CH2:14][Cl:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)CCl)OCc1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O=C(N[C@@H](Cc1ccc(F)cc1)[C@@H](O)CCl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
(3S)-3-Benzyloxycarbonylamino-1-chloro4-(p-fluorophenyl)-2-butanone (174.9 mg, 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.34 mg, 0.0005 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (2R,3S)-3-benzyloxycarbonylamino-1-chloro-2-hydroxy-4-(p-fluorophenyl)butane (166.2 mg; yield: 94.4%). As a result of HPLC analysis, the production ratio of the desired (2R,3S)-form to the isomeric (2S,3S)-form, (2R,3S):(2S,3S), was 6.7:1. The results of elementary analysis were as follows.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([CH3:22])[C:20]2[C:23]([Br:28])=[C:24]([F:27])[CH:25]=[CH:26][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl>[Br:28][C:23]1[C:20]2[N:21]([CH3:22])[C:17]([C@@H:15]([NH2:14])[CH3:16])=[N:18][C:19]=2[CH:26]=[CH:25][C:24]=1[F:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(Br)c2n1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)c(Br)c2n1C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
TFA (40 mL) was added to a solution of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (3.02 g, 8.11 mmol) in DCM (20 mL) and stirred for 15 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (2.04 g, 92%). LCMS (Method C): RT 1.83 min [M+H]+ 271.9, 273.9
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:26][O:27][CH2:28][CH2:29][NH2:30]>>[CH2:22]([C:18]([NH:17][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:16])([C:19](=[O:21])[NH:30][CH2:29][CH2:28][O:27][CH3:26])[CH2:24][CH3:25])[CH3:23]
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Reactant: COCCN
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)NCCOC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and 2-methoxyethanamine (CAN 109-85-3) as starting materials. MS (EI): m/e=404.4 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:12]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:14][C:13]=1[C:23]([O:25]CC)=O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O.[O-]CC.[Na+].O>C(O)C.CCOC(C)=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]2[CH2:3][CH2:2][NH:1][C:23](=[O:25])[C:13]3[S:14][C:15]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:16][C:12]2=3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(N2CCOCC2)cc1C(CCN)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1NCCC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.9 %

Procedure:
A 100 mL rbf was charged with a solution of ethyl 3-[3-amino-1-(4-chlorophenyl)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate.TFA (842 mg, 1.61 mmol) in ethanol (10.0 mL) and 21% sodium ethoxide (21:79, Sodium ethoxide: ethanol, 4.81 mL, 12.9 mmol). The rbf was equipped with a reflux condenser and the reaction was heated to 80° C. In 3 h, the solution was cooled and distributed between water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined org layer was washed with brine (×2), dried, and concentrated to provide a yellow solid. Purification on a silica gel column (continuous gradient from CH2Cl2 to 8% MeOH/CH2Cl2) provided 420 mg of 4-(4-chlorophenyl)-2-(morpholin-4-yl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as a yellow solid (71.9% yield). LCMS: (AA) ES+ 363, 365; 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.71 (s, 1H), 7.41-7.32 (m, 2H), 7.18-7.09 (m, 2H), 5.64-5.55 (s, 1H), 4.38-4.27 (dd, J=7.9, 5.1 Hz, 1H), 3.70-3.58 (t, J=4.9 Hz, 4H), 3.14-3.06 (d, J=4.3 Hz, 2H), 3.06-2.96 (t, J=4.9 Hz, 4H), 2.24-2.13 (m, 1H), 2.03-1.90 (m, 1H). Racemic 4-(4-chlorophenyl)-2-(morpholin-4-yl)-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one (0.42 g) was separated into enantiomers on a Chiralpak IA 30×250 mm 5 micron column using a 60/40/0.1 Hexane-EtOH-DEA mixture and a flow rate of 35 mL/min. Peak one (195 mg) was collected with retention times of 10-18 min and peak two (208 mg) was collected with retention times of 26.5-38.5 min. Absolute configuration of the obtained enantiomers is unknown.
Reaction SMILES: [CH:1]1([C@H:6]2[C:33](=[O:34])[N:32]3[CH2:35][C@@H:29]([CH2:30][C@H:31]3[C:36]([NH:38][C@:39]3([C:44](=[O:52])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[CH2:41][C@H:40]3[CH:42]=[CH2:43])=[O:37])[O:28][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([OH:27])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:53][CH2:54][CH2:55][C@H:10]3[O:9][C:8](=[O:56])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[P:64](Cl)([O:69][CH2:70][CH3:71])([O:66][CH2:67][CH3:68])=[O:65]>ClCCl>[P:64]([O:69][CH2:70][CH3:71])([O:66][CH2:67][CH3:68])([O:27][C:26]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=[C:18]2[O:28][C@H:29]3[CH2:35][N:32]([C:33](=[O:34])[C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[NH:7][C:8](=[O:56])[O:9][C@@H:10]4[CH2:55][CH2:54][CH2:53][C@H:11]4[CH2:12][CH2:13][CH:14]=[CH:15][CH2:16][C:17]=12)[C@H:31]([C:36](=[O:37])[NH:38][C@:39]1([C:44](=[O:52])[NH:45][S:46]([CH:49]2[CH2:50][CH2:51]2)(=[O:47])=[O:48])[CH2:41][C@H:40]1[CH:42]=[CH2:43])[CH2:30]3)=[O:65]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Reactant: CCOP(=O)(Cl)OCC
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1O)O2)C(=O)NS(=O)(=O)C1CC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/Cc1c(nc3ccccc3c1OP(=O)(OCC)OCC)O2)C(=O)NS(=O)(=O)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CCc1c(nc3ccccc3c1OP(=O)(OCC)OCC)O2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C

Procedure:
To a solution of (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-19-hydroxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide (Example 17) (35 mg) in dichloromethane (0.44 mL) was added triethylamine (123 μl) followed by diethyl chlorophosphate (64 μl). The reaction mixture was stirred at room temperature until disappearance of the starting material. The reaction was quenched with water and extracted with ethyl acetate (3×). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (40-100% ACN/0.015% TFA-water) afforded the desired product (20 mg). LRMS (ES+) m/z 926.4 (M+H)+.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[CH:25]=[C:24]([CH2:26]Cl)[CH:23]=[CH:22][N:21]=2)=[CH:14][C:13]=1[O:28][CH3:29]>>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([CH2:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([C:15]4[CH:16]=[C:17]([O:18][CH3:19])[C:12]([Cl:11])=[C:13]([O:28][CH3:29])[CH:14]=4)[CH:25]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1Cl
Product: COc1cc(-c2cc(CN3CCC4(CC3)OCCO4)ccn2)cc(OC)c1Cl

Procedure:
4-Piperidone ethylene ketal (573 mg) and 2-(4-chloro-3,5-dimetoxyphenyl)-4-chloromethylpyridine (1.19 g) were condensed in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:15]#[N:16])([O:13][CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:16][CH2:15][C:10]1([O:13][CH3:14])[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1
Reactant: COC1(C#N)CCN(Cc2ccccc2)C1
Agent: [Ni]
Solvent: CO
Product: COC1(CN)CCN(Cc2ccccc2)C1

Procedure:
The solution of 26.5 g (0.11 mol, 93% proof) 1-benzyl-3-cyano-3-methoxypyrrolidine in 300 ml methanol is hydrogenated at 15 g Raney-Ni at 60° C./100 bar H2. The catalyst is removed by filtration, the methanol is removed in vacuo, and the residue is distilled.
Reaction SMILES: [CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].S1C=CC=C1B(O)[OH:36]>>[OH:36][CH2:3][CH2:2][CH2:1][C@@:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3cccs3)cc2)C(=O)O1
Reactant: OB(O)c1cccs1
Product: C[C@@H](c1ccc(-c2cccs2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-allyl-6-phenyl-3-((S)-1-(4-(thiophen-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and thiophene-2-boronic acid using a procedure analogous to that described in Example 64 followed by a procedure analogous to that described in Example 78. LC-MS Method 2 tR=2.47, min, m/z=422; 1H NMR (CDCl3) 1.49 (d, 3H), 1.84-1.92 (m, 2H), 2.0-2.15 (m, 4H), 2.25 (m, 2H), 2.84 (m, 1H), 3.52 (m, 1H), 4.20 (m, 1H), 5.60 (m, 1H), 6.82 (dd, 2H), 7.0 (m, 1H), 7.15-7.38 (m, 9H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]3[C:17]=2[CH2:18][CH2:19][C@H:20]3[O:26][C:27]2[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=2)=[C:11]([CH3:41])[CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C>[F:25][C:22]1[CH:23]=[CH:24][C:16]([C:12]2[C:13]([CH3:15])=[CH:14][C:9]([OH:8])=[CH:10][C:11]=2[CH3:41])=[C:17]2[C:21]=1[C@H:20]([O:26][C:27]1[CH:40]=[CH:39][C:30]3[C@H:31]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH2:32][O:33][C:29]=3[CH:28]=1)[CH2:19][CH2:18]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[Si](C)(C)C(C)(C)C)cc5C)ccc(F)c43)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O)cc5C)ccc(F)c43)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-((S)-6-((R)-4-(4-(tert-butyldimethylsilyloxy)-2,6-dimethylphenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (440 mg) in tetrahydrofuran (5 mL) is added at 0° C. tetrabutylammonium fluoride (3.1 mL of a 1 M solution in tetrahydrofuran). The mixture is stirred for 2 hours at room temperature, diluted with diethylether and washed with water and brine. After drying (MgSO4) the solvents are evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 90:10→60:40) to give the title compound. Yield: 280 mg; LC (method 4): tR=1.79 min; Mass spectrum (ESI+): m/z=485 [M+Na].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>O1CCOCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:4][N:3]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)c1cnc(Cl)nc1C(F)(F)F
Reactant: Nc1cccc(Cl)c1
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of benzyl 2-chloro-4-trifluoromethylpyrimidine-5-carboxylate (0.50 g, ex Maybridge) in 1,4-dioxan (5 ml) was added 3-chloroaniline (0.85 ml) and the solution stirred at room temperature for 15 h. 1,4-Dioxan was removed under reduced pressure and ethyl acetate (15 ml) added. The solution was washed sequentially with 2N hydrochloric acid (10 ml) and water (3×10 ml), dried (MgSO4), evaporated and triturated with hexane to afford benzyl 2-(3-chlorophenylamino)-4-trifluoromethylpyrimidine-5-carboxylate (524 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:15]2[S:24][C:23]3[C:22]4[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:21]=4[O:20][CH2:19][CH2:18][C:17]=3[CH:16]=2)[N:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[F:14])[N:6]=1.Cl.[NH2:33][CH:34]1[CH2:37][O:36][CH2:35]1>>[O:36]1[CH2:37][CH:34]([NH:33][C:29]([C:27]2[CH:26]=[CH:25][C:22]3[C:23]4[S:24][C:15]([C:4]5[N:5]([C:7]6[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=6[F:14])[N:6]=[C:2]([NH2:1])[N:3]=5)=[CH:16][C:17]=4[CH2:18][CH2:19][O:20][C:21]=3[CH:28]=2)=[O:30])[CH2:35]1
Reactant: NC1COC1
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccc(F)cc2F)n1
Agent: Cl
Product: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)NC4COC4)cc2OCC3)n(-c2ccc(F)cc2F)n1

Procedure:
Similarly to as described in General Procedure D, 2-[5-Amino-2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-8-carboxylic acid was reacted with 3-aminooxetane hydrochloride to give 297 as a colorless solid after reverse phase HPLC (146 mg). LCMS: 496.1
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:31][CH2:32][CH2:33][CH3:34])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([O:26]C(C)(C)C)=[O:25])=[CH:14][CH:13]=2)[C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2].Cl>O1CCOCC1>[C:1]([C:4]1[N:5]=[C:6]([CH2:31][CH2:32][CH2:33][CH3:34])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([OH:26])=[O:25])=[CH:14][CH:13]=2)[C:8]=1[C:9]#[N:10])(=[O:3])[CH3:2]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A solution of 1.3 g of 4-acetyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-cyanoimidazole [prepared as described in step (a) above] in 30 ml of a 4N solution of hydrogen chloride in dioxane was allowed to stand overnight at room temperature, after which it was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give a colorless amorphous solid. The solid was triturated in hexane, collected by filtration and dried, to give 1.1 g of the title compound, melting at above 55° C. (with softening).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[N:14][C:15]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[CH:16][CH:17]=2)[CH2:7][CH2:6]1)=[O:4].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:30][S:27]([C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([C:15]1[N:14]=[CH:13][C:12]([O:11][CH:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:6][CH2:7]3)=[CH:17][CH:16]=1)[CH:19]=[CH:20]2)(=[O:28])=[O:29]
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CCl)CC3)cn2)c1
Product: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)CN4CCCCC4)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-196 using 2-chloro-1-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)ethanone and piperidine (0.045 g, 50.56%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:27]([CH2:2][C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]([O:23][CH3:24])[CH:9]=2)[N:4]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(-c2nc(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Product: COc1ccc(-c2nc(CNc3ccccc3)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Example 56, 2-chloromethyl-4- (3,4-dimethoxyphenyl ) -6,7-dimethoxyquinazoline was reacted with aniline to give 2-anilinomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline. This compound was recrystallized from ethanol. Colorless prisms, mp. 199°-200° C.