Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([NH:22][CH2:23][C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: O=C(O)c1[nH]c(-c2cccs2)cc1-c1ccc(F)cc1
Reactant: COC(=O)c1cnc(CN)cn1
Agent: Cl
Product: COC(=O)c1cnc(CNC(=O)c2[nH]c(-c3cccs3)cc2-c2ccc(F)cc2)cn1
Yield: 76 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrole-2-carboxylic acid and methyl 5-(aminomethyl)pyrazine-2-carboxylate hydrochloride, yielding the title compound. Methyl 5-[({[3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]pyrazine-2-carboxylate: Yield 76%; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.47 (sb, 1H), 9.07 (s, 1H), 8.64 (s, 1H), 7.47 (dd, J=8.3 Hz, J′=5.5 Hz, 2H), 7.24 (d, J=4.5 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 7.16 (t, J=8.6 Hz, 2H), 7.06 (dd, J=4.5 Hz, J′=4.1 Hz, 1H), 6.64 (t, J=4.6 Hz, 1H), 6.40 (d, J=2.9 Hz, 1H), 4.72 (d, J=5.2 Hz, 2H), 4.04 (s, 3H).
Reaction SMILES: [BH4-].[Na+].O.[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH:36]=[O:37])[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)(=[O:7])[CH:5]=[CH2:6]>O1CCOCC1>[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH2:36][OH:37])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[CH:20][CH:21]=1)(=[O:7])[CH:5]=[CH2:6]
Reactant: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCC=O)CC3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=CC(=O)OCCCCCCOc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.123 g of sodium borohydride and 10 ml of water was treated dropwise at 20° C. with a solution of 5.00 g of 6-[4'-[trans-4-(3-oxo-propyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate in 50 ml of dioxan. The mixture was subsequently stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml of water, the phases were separated and the aqueous phase was extracted twice with 25 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate, filtered and concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) gave 4.77 g of 6-[4'-[trans-4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-yloxy]-hexyl acrylate.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH2:31]1[CH:39]2[N:34]([CH2:35][CH2:36][C:37](=[O:40])[CH2:38]2)[CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[NH:4][N:3]=[C:2]([C:37]3([OH:40])[CH2:38][CH:39]4[N:34]([CH2:33][CH2:32][CH2:31]4)[CH2:35][CH2:36]3)[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCN2CCCC2C1
Reactant: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CCN2CCCC2C1
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
3-Bromo-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (3.18 g (10 mmol), prepared as described in 1)) was dissolved in tetrahydrofuran (32 ml). To the solution was added a solution of 1.6 M butyl lithium/hexane (13.75 ml, 13.75 mmol) at −78° C., and the resulting mixture was stirred for 10 minutes. To the mixture was added 1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (1.53 g, 11 mmol) at −78° C., and the resulting mixture was stirred first at −78° C. for 2 hours, then at room temperature for 1 hour. At the end of this time, the reaction mixture was added to a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=20:1:1), to give the title compound (830 mg) as a pale yellow powder (yield 22%).
Reaction SMILES: [CH:1]1([S:7]([CH2:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([N:34]=[N+:35]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[CH:1]1([S:7]([C:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[N+:34]=[N-:35])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1ccc(S(=O)(=O)CS(=O)(=O)C2CCCCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 38 %

Procedure:
The cyclohexylsulfonyl(4-methanesulfonyloxyphenylsulfonyl)methane in Synthesis Example 12, 10 g (0.025 mol), was dispersed in 150 g of dichloromethane. To the dispersion was added 4.6 g (0.03 mol) of p-toluenesulfonylazide. With stirring under ice cooling, 4.9 g (0.025 mol) of DBU was added to the dispersion, and after 10 minutes, 100 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 13 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 20 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 4.0 g (yield 38%) of fine yellow crystals.
Reaction SMILES: [C:1]([C:3]([CH3:14])([CH3:13])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)#[N:2].C([O-])([O-])=O.[K+].[K+].OO.[OH2:23]>CS(C)=O>[C:3]([O:11][C:10]([N:7]1[CH2:8][CH2:9][N:4]([C:3]([C:1](=[O:23])[NH2:2])([CH3:14])[CH3:13])[CH2:5][CH2:6]1)=[O:12])([CH3:14])([CH3:13])[CH3:1]
Reactant: CC(C)(C#N)N1CCN(C(=O)O)CC1
Reactant: O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(N)=O)CC1
Temperature: 40 °C

Procedure:
To a cooled (ice/water bath) solution of 4-(cyano-dimethyl-methyl)-piperazine-1-carboxylic acid tent-butyl ester (102.9 mg) in dry DMSO was added K2CO3 (9.8 mg) followed by 28% hydrogen peroxide solution (200 μL) dropwise. The resultant was heated at 40° C. overnight. Water was added and the white solid collected, washed with water and air dried to give 4-(1-carbamoyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (59.6 mg). (See Tetrahedron 2002, 58, 3217). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C@H:8]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:9][CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Si:18]([O:17][C@H:8]([CH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:7][O:6][C:5]1[CH:25]=[CH:26][C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:3][C:4]=1[C:27]([F:30])([F:29])[F:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(Br)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 108 %

Procedure:
Prepared according to the method as described in Example 33a) from (2R)-1-(4-bromo-2-trifluoromethylphenoxy)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)butane (1.0 g, ~67% pure), benzeneboronic acid (0.18 g), tetrakis(triphenylphosphine)palladium(0) (0.035 g), toluene (10 ml), ethanol (2 ml) and aqueous sodium carbonate (2 M, 1.45 ml) with heating at 120° C. for 1 hour. After work up the residue was purified by chromatography over silica eluting with ethyl acetate:hexane (1:9) to give an impure sample of the sub-title compound as a light brown oil (0.80 g, ~67% pure).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH3:17].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)c(Cl)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C
Yield: 94.3 %

Procedure:
To a solution of methyl 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (7.6 g, 28.1 mmol) in THF/H2O (30 mL/5 mL) was added KOH (4.72 g, 84 mmol). The reaction mixture was heated to 50° C. for 1 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (50 mL×3). The collected organic layers were concentrated under vacuum to give the crude acid (6.8 g, 94%), which was used directly in the next step without further purification: LCMS (ES) m/z 257 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13](=[O:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:18][CH2:19][CH:14]([C:13]([O:12][CH3:11])=[O:20])[CH2:15][CH2:16]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCNCC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1CCN(Cc2ccc(OC)cc2)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
4-Methoxybenzyl chloride (1.10 g, 6.98 mmol) was added dropwise to a solution of isonipecotic acid methyl ester (1.00 g, 6.98 mmol) and triethylamine (1.40 g, 14 mmol) in THF (30 ml) and the mixture was stirred at 60° C. for 72 h. 5% strength sodium bicarbonate solution (50 ml) was then added to the reaction mixture and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue was purified by flash chromatography with cyclohexane/ethyl acetate (2:1).
Reaction SMILES: [CH:1]1([C@@H:4]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:22])[CH2:3][CH2:2]1.BrC1C=CC([C@H](C2CC2)N2CC[C@](CC(O)(C)C)(C3C=CC=CC=3)OC2=O)=CC=1.Cl[C:68]1[N:69]=[N:70][C:71]([CH3:74])=[CH:72][CH:73]=1>>[CH:1]1([C@@H:4]([C:23]2[CH:28]=[CH:27][C:26]([C:68]3[N:69]=[N:70][C:71]([CH3:74])=[CH:72][CH:73]=3)=[CH:25][CH:24]=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:7][C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Agent: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Product: Cc1ccc(-c2ccc([C@H](C3CC3)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 3-chloro-6-methyl-pyridazine following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.39 min; Mass spectrum (ESI+): m/z=472 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][C:7](=[O:31])[C:6]=2[CH:32]=1.O.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:30])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[CH:15][C:14]=3[CH3:29])[CH2:10][CH2:9][CH2:8][CH:7]([OH:31])[C:6]=2[CH:32]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3cc(Cl)ccc32)c(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
7-chloro-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-5 oxo-2,3,4,5-tetrahydro-1H-1-benzazepine (5 gm,) was suspended in methanol(40 ml) & water (6 ml) and then added sodium borohydride (0.211 gm.) at 30° C. and the reaction mixture was stirred for 1 hr. To the reaction mixture was added hydrochloric acid (30 ml). Then the reaction mixture was stirred for 2 hours, The solid obtained was collected by filtration and dried to give 7-chloro-5-hydroxy-1-[2-methyl-4-(2-methyl benzoyl amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (4.55 gm).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[C:4]#[N:5].[N:14]1[CH:19]=[CH:18][C:17]([C:20]2([CH2:25][C:26](O)=[O:27])[NH:24][CH:23]=[CH:22][S:21]2)=[CH:16][CH:15]=1>>[C:4]([C:3]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([O:10][CH3:11])=[CH:9][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][C:20]1([C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[NH:24][CH:23]=[CH:22][S:21]1)#[N:5]
Reactant: O=C(O)CC1(c2ccncc2)NC=CS1
Reactant: COc1cc(N)c(C#N)cc1OC
Product: COc1cc(C#N)c(NC(=O)CC2(c3ccncc3)NC=CS2)cc1OC

Procedure:
This compound was prepared according to the method described in Example 1c by employing 2-amino-4,5-dimethoxybenzonitrile (Aldrich) and 2-(4-pyridyl)-thiazole acetic acid (Example 1, Step b) . Mp: 165-167° C. MS m/z: 381.1 (M+1). Calc'd for C19H16N4O3S: 380.09.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][NH:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:51]#N.[Na+].CCOC(C)=O>CC(O)=O>[C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:51])[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C12CNOC(C(n3ccc(=O)[nH]c3=O)O1)C2OCc1ccc2ccccc2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2OCc1ccc2ccccc2c1

Procedure:
To a solution of compound 52 (1 mmol) in CH3COOH (5 mL) and trithylortoformate (1 mL), 20% aq. HCHO (0.16 mL, 1.1 mmol) was added at 0° C. After 15 minutes NaBH3CN (2 mmol) is added. After an additional 1 hour the mixture is poured into EtOAc (250 mL), washed with saturated aqueous NaHCO3 (2×250 mL), dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel chromatography gave compound 53 in 90% isolated yield.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:23]=1)[C:20](Cl)=[O:21]>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([C:20]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)=[O:21])[CH:23]=1
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: CCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: -2.5 °C
Reaction time: 1 h

Procedure:
At −5-0° C., ethoxybenzene (20.5 g) and AlCl3 (22.3 g) were added into a solution of 5-bromo-2-chlorobenzoyl chloride (from step 2) in dry DCM (200 mL). Then the mixture was stirred at −5-0° C. for 1 h. The mixture was poured into ice-H2O (200 mL) and extracted with DCM. The organic phase was washed with 1M HCl, H2O, IM NaOH and brine. And the organic phase was concentrated, and the crude was purified by silica-gel column chromatography (PE/EA=80/1-40/1), to obtain 30 g of (5-bromo-2-chloro phenyl)(4-ethoxyphenyl)methanone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]3[C:15]=2[CH2:16][NH:17][C:18](=[O:34])[N:19]3[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCOCC>Cl.C(O)C>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][N:19]1[C:20]2[C:15](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=2)[CH2:16][NH:17][C:18]1=[O:34]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)N(Cc1cccc(F)c1)C(=O)NC2
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1cc(N2CCNCC2)c2c(c1)N(Cc1cccc(F)c1)C(=O)NC2
Temperature: 80 °C

Procedure:
4-[1-(3-Fluoro-benzyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (43 mg) was dissolved in 4 mL 2N HCl/ethanol and heated to 80° C. for 20 minutes. The reaction mixture was cooled to room temperature, and ether was added, precipitating 18 mg of 1-(3-fluoro-benzyl)-7-methoxy-5-piperazin-1-yl-3,4-dihydro-1H-quinazolin-2-one. MS: 371 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.Cl.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[CH2:28][CH2:29]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: c1csc(CN2CCNCC2)c1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: O=C(N1CCN(Cc2cccs2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 18.5 %

Procedure:
The title compound of Example 2 (0.93 g, 3.20 mmol) was reacted with the product of Example 52 (0.57 g, 3.20 mmol) by the method of Example 4 with the modification described in Example 32. Following chromatographic separation, 0.26 g of the white solid title product was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8]O)[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13].S(Cl)([Cl:17])=O.CN(C)C=O.C(=O)(O)[O-].[Na+]>O>[O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][Cl:17])[NH:5][CH:4]=[C:3]1[O:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COc1c[nH]c(CO)cc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1c[nH]c(CCl)cc1=O
Reaction time: 0.5 h

Procedure:
To crystals (10 g) of 2 -(4-oxo-6-hydroxymethyl-1,4-dihydropyridin-3-yloxy)acetic acid was added thionyl chloride (25 ml), and the mixture was stirred for 30 minutes. After cooling, dimethylformamide (125 ml) was added to the reaction mixture, and the resultant mixture was stirred for an hour. The resultant mixture was poured into cold water (750 ml) and the aqueous solution was adjusted to pH 3 with an aqueous sodium bicarbonate solution and then cooled with ice for 2 hours. Precipitated crystals were collected by filtration and washed with water to give crystals (8.7 g) of 2-(4-oxo-6-chloromethyl-1,4-dihydropyridin-3-yloxy)acetic acid. (This product was converted to its hydrochloride monohydrate, m.p. 150° to 155° C. by recrystallizing from a mixture of 10% hydrochloric acid (5 ml) and water (5 ml).)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]3[N:24]=[CH:25][C:26]([C:27](O)=[O:28])=[C:16]3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[OH:30][CH2:31][C:32]([NH:35][S:36]([C:39]1[S:43][C:42]([NH2:44])=[N:41][C:40]=1[CH3:45])(=[O:38])=[O:37])([CH3:34])[CH3:33]>>[OH:30][CH2:31][C:32]([NH:35][S:36]([C:39]1[S:43][C:42]([NH:44][C:27]([C:26]2[CH:25]=[N:24][N:17]3[C:18]([C:20]([F:21])([F:22])[F:23])=[CH:19][C:14]([C:6]4[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)=[N:15][C:16]=23)=[O:28])=[N:41][C:40]=1[CH3:45])(=[O:38])=[O:37])([CH3:34])[CH3:33]
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Reactant: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4nc(C)c(S(=O)(=O)NC(C)(C)CO)s4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.10) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Light yellow solid. MS (ISP) 665.2 [(M−H)−]; mp 276° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1.O1CCOCC1.CS(O)(=O)=O>C(OCC)(=O)C>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[N:23]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccnc(Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)n1
Temperature: 100 °C
Yield: 57.7 %

Procedure:
To a flask containing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.50 g, 6.85 mmol) and 2-chloro-4-methylpyrimidine (1.01 g, 7.87 mmol) were added dioxane (69 mL) and methanesulfonic acid (0.51 mL, 7.87 mmol). The reaction was heated at 100° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield 4-methyl-N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (1.23 g, 3.95 mmol, 58% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>C1COCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: OC(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroacetophenone (6.25 g., 40.4 mmol) was treated with (+) DIP-chloride (18 g., 56.1 mmol) in anhydrous THF (40 mL) at dry-ice bath temperature and left overnight. The temperature was raised to room temperature and THF was removed in vacuo. The residue was dissolved in ether (210 mL). The diethanolamine (9 g., 8 5.6 mmol) was added and the mixture stirred at room temperature for 5 hrs. The separated solid was filtered and the filtered cake was washed with ether (150 mL). The combined filtrates were evaporated to dryness to give 15.53 g. of crude product. This was purified by silica gel column chromatography using 1% ether and petroleum ether 4.32 g (68%) of the desired product as an oil.