Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:32]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:18]([N:17]([CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][CH2:32][C:28]3[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=3)=[CH:25][CH:24]=2)=[CH:11][CH:12]=1)[CH2:21][CH2:22][CH3:23])[CH2:19][CH3:20]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Reaction time: 22 h
Yield: 69.3 %

Procedure:
The compound (290.2 mg) obtained in Example 122-3 was dissolved in methanol (8.71 ml) and added with 1-methyl-2-imidazole carboxaldehyde (141.2 mg) and trimethyl orthoformate (272.2 mg), followed by stirring for 22 hours. The reaction solution was cooled with ice and then added with sodium borohydride (97.0 mg), followed by stirring at room temperature for 0.5 hour. The reaction solution was concentrated under reduced pressure and the residue was then added with water, followed by separation/extraction with chloroform. The organic layer was washed with saturate saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (256.8 mg) as a yellow oily substance.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.CN(C)C=O.[OH-].[NH4+]>O>[N:16]1([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=3)[N:4]=[C:3]([CH3:2])[CH:12]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc2nc(C)cc(Cl)c2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(C)cc(-n3cncn3)c2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of 2.44 g of 2-methyl-4-chloro-6-methoxy-quinoline-hydrochloride, 1.38 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 80° C. for 3 hours whereupon the reaction mixture is poured into 100 ml of water and neutralized with 2 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered. Thus 2.09 g of the desired compound are obtained, yield 87%, mp.: 117°-118° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:14][CH2:15][CH:16]=[CH2:17])[CH:12]=[CH2:13].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]([CH2:15][CH:16]=[CH2:17])[CH2:11][CH:12]=[CH2:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C=CCNCC=C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCN(CC=C)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 59.5 %

Procedure:
A mixture of 4-fluoronitrobenzene (5.00 g, 35.44 mmol), diallylamine (3.48 g, 4.4 ml, 35.44 mmol) and K2CO3 (5.39 g, 38.98 mmol) in dry DMSO (40 ml) was heated at 100° C. under an atmosphere of argon for 3 h. The reaction mixture was then left to cool to room temperature (23° C.) and added to water (300 ml) and extracted with EtOAc (4×75 ml). The combined organics were washed with brine (100 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a red oil that was purified by chromatography (2:1 Hexane/DCM) to give the title compound (4.60 g, 59%) as an orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[S:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1csc(-c2cccs2)n1
Product: c1csc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)cs2)c1
Yield: 79 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-thienyl)thiazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)thiazole. The yield was 79%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 76-77° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([OH:19])=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1C=CC=CC=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30](C(=O)CBr)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:1][O:8][C:9]2[CH:18]=[C:17]3[C:12](=[CH:11][CH:10]=2)[CH:13]=[CH:14][C:15]([OH:19])=[CH:16]3)[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccc2ccc(OCc3ccccc3)cc2c1
Reactant: O=C(CBr)N1CCC(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Oc1ccc2ccc(OCCN3CCC(Cc4ccccc4)CC3)cc2c1

Procedure:
The title compound was prepared from 7-benzyloxy-naphthalen-2-ol (1.00 g, 4.00 mmol), 1-(4-benzyl-piperidin-1-yl)-2-bromo-ethanone (1.20 g, 4.05 mmol) and potassium carbonate (1.10 g, 7.96 mmol) in tetrahydofuran (40 ml) in three steps as a solid, mp 159-160° C. Analysis calculated for C24H27NO2 ·0.16H2O: C, 79.11; H, 7.56; N, 3.85. Found: C, 79.11; H. 7.63; N, 3.83.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]=[N:33][N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:35]=2)=[CH:21][CH:20]=1)O)[CH2:2][CH2:3][CH3:4]>[Pd].C(O)(=O)C.C1COCC1>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH2:17][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[N:32]=[N:33][NH:34][N:35]=2)=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(C(O)c2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C(=O)O)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCn1c(Cc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C(=O)O)c2ccccc21
Yield: 75.6 %

Procedure:
A mixture of 1-butyl-2-{2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-biphenyl-4-yl(hydroxy)methyl}-1H-indole-3-carboxylic acid (2.5 g, 3.52 mmol) and 10% palladium on carbon (1.2 g) in 20 mL of acetic acid and 80 mL of THF under a hydrogen atmosphere (200 psi) at 48° C. for approximately 48 hours. The mixture was then cooled, filtered and diluted with 500 mL of water. The mixture was extracted with 100 mL of ethyl acetate and the ethyl acetate layer was washed three times with water. The ethyl acetate layer was concentrated to give 1-butyl-2-[2'-(2H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-indole-3-carboxylic acid (1.2 g, 2.66 mmol).
Reaction SMILES: [C:1]1(=[O:27])[N:5]([CH2:6][C:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=23)[C:4](=[O:22])[C:3]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:2]12.C(O)=O.[H][H]>CN(C)C=O.[Pd]>[C:4]1(=[O:22])[N:5]([CH2:6][CH:7]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[C:1](=[O:27])[C:2]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:3]12
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1CC1=c2ccccc2=Cc2ccccc2N1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=CO
Product: O=C1c2ccccc2C(=O)N1CC1Nc2ccccc2Cc2ccccc21
Temperature: 50 °C

Procedure:
A suspension of 110.0 kg of 6-phthalimidomethyl-5H-dibenz[b,e]azepine in 911.4 liters of dimethylformamide, 28.7 kg of formic acid and a suspension of 12.5 kg of 10% palladium charcoal in 25 liters of dimethylformamide is fed into a 1200 liter VA-propulsive jet loop reactor. The reaction mixture is heated to 70° C. and hydrogenated under 7 bar of absolute hydrogen pressure. After the catalyst has been filtered off and the reaction equipment and catalyst have been washed with 80 liters of dimethylformamide, 960 liters of dimethylformamide are distilled off from the combined filtrates at 70° to 80° C. After cooling to 50° C., 150 liters of acetone are added, then after further cooling to 15° C. the precipitated crystals are centrifuged off, washed with acetone and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.N1C=CC=CC=1.[Cl:24][CH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31](Cl)=[O:32])[N:30]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:31]([C:29]2[N:30]=[C:26]([CH2:25][Cl:24])[S:27][CH:28]=2)=[O:32])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Reactant: O=C(Cl)c1csc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(Br)cc2nn(C3CCCCO3)cc12)c1csc(CCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (1.47 g) in DCM (20 ml) was added pyridine (1 ml). The reaction mixture was stirred for 5 minutes at room temperature before 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.21 g) in DCM (20 ml) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate solution (40 ml) was added and the reaction was stirred vigorously before the organic layer was separated using a hydrophobic frit. The aqueous layer was extracted with further DCM and the combined organic layers were evaporated to dryness. The residual solid was dried on a high vacuum line before triturating with cyclohexane to give the title compound (1.52 g).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2=[C:8]([NH2:11])[CH:9]=[N:10][N:6]2[CH2:5][C@@H:4]([CH3:12])[O:3]1.C(OC[C@@H](O)C)C1C=CC=CC=1>>[CH3:1][CH:2]1[C:7]2=[C:8]([NH2:11])[CH:9]=[N:10][N:6]2[CH2:5][C@H:4]([CH3:12])[O:3]1
Reactant: CC1O[C@H](C)Cn2ncc(N)c21
Agent: C[C@H](O)COCc1ccccc1
Product: CC1O[C@@H](C)Cn2ncc(N)c21

Procedure:
(6S)-4,6-Dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-amine was prepared in a manner analogous to that of (6R)-4,6-dimethyl-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-3-amine, starting from (2S)-1-benzyloxypropan-2-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CN(C)C=O.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>[CH3:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:17]=1)[CH3:15]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cncc(Br)c1
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: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cncc(-c2ccc(C(C)C)cc2)c1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
4.68 g (20.32 mmol) of ethyl 5-bromonicotinate, 5.00 g (30.49 mmol) of 4-(1-methylethyl)-phenylboronic acid, 0.12 g (0.10 mmol) of tetrakis(triphenylphosphine)palladium(0) and 4.31 g (40.65 mmol) of sodium carbonate were dissolved in a mixture of 37 ml of 1,2-dimethoxyethane, 10.5 ml of water and 84 ml of dimethylformamide and stirred at 85° C. for 18 h. For work-up, some of the dimethylformamide was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the crude product was purified by preparative HPLC. Yield: 2.42 g (44% of theory)
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:20].[Na+:21].O>O1CCOCC1>[NH2:3][C:4]1[C:5]([O:11][C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:20])=[O:1].[Na+:21]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(Oc3c(Cl)cccc3Cl)c2N1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(CC(=O)[O-])cccc1Oc1c(Cl)cccc1Cl

Procedure:
A mixture of 2-oxo-7-(2,6-dichlorophenoxy)indoline (3.4 g.), sodium hydroxide (1.86 g.) and water (50 ml.) was refluxed under heating for 120 hours with stirring. Insoluble starting material (2.5 g.) was recovered by filtration and the filtrate was cooled. The precipitates were collected by filtration and washed with a small amount of water and diethyl ether in turn to give the captioned compound (1.35 g.). Further, to the above obtained insoluble material (2.5 g.) were added sodium hydroxide (2 g.) and 50% dioxane (50 ml.), and the mixture was stirred for 70 hours and filtered. After cooling, the precipitates were collected by filtration and washed with water and diethyl ether in turn to give the same captioned compound (1.3 g.). Total yield (2.65 g.). mp>230° C.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]=1[C:13]([N:15]1[CH2:24][CH2:23][CH2:22][C@H:16]1[C:17]([O:19]CC)=[O:18])=[O:14]>C(O)C>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]=1[C:13]([N:15]1[CH2:24][CH2:23][CH2:22][C@H:16]1[C:17]([OH:19])=[O:18])=[O:14]
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)C1=Cc2ccccc2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN1C(=O)C1=Cc2ccccc2CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 50% aqueous ethanol solution (100 ml) containing potassium hydroxide (2.56 g, 0.039 mmole), (10a) (9.09 g, 0.030 mole) is added, and the mixture is stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture is concentrated to the one-fourth of the amount under reduced pressure, and the resultant aqueous alkaline solution is washed with ether (50 ml×2). The aqueous alkaline layer is adjusted to about pH 2 with conc. hydrochloric acid, and the precipitated product is extracted with ethyl acetate (150 ml×2). The ethyl acetate layers are combined, washed with a saturated aqueous solution of sodium chloride (30 ml×2) and dried over anhydrous magnesium sulfate. After filtration and evaporation, a pure product (11a) is obtained as a colorless caramel (8.1 g, 98%). [α]D20 -93.3° (c=2.16, chloroform). IRνmaxNujol cm-1 : 1730 (COOH), 1630 (C=C), 1570 (CON). NMR (in CDCl3): 1.73-2.43 (4H, m, NCH2CH2CH2), 2.43-3.15 (4H, m, CH2CH2C=), 3.69 (2H, t, J=6Hz, NCH2), 4.60 (1H, t, J=7Hz, NCHCO2), 6.75 (1H, s, CH=C), 7.09 (4H, s, aromatic proton), 8.65 (COOH).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:9]=[C:10]([CH2:34][CH2:35][C:36](OCC)=[O:37])[CH:11]=[C:12]([F:33])[C:13]=1[O:14][CH2:15][C:16]1[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:18][S:19][C:20]=1[C:21]([F:24])([F:23])[F:22]>>[F:7][C:8]1[CH:9]=[C:10]([CH2:34][CH2:35][CH2:36][OH:37])[CH:11]=[C:12]([F:33])[C:13]=1[O:14][CH2:15][C:16]1[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:18][S:19][C:20]=1[C:21]([F:24])([F:22])[F:23]
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(OC)cc3)nsc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2c(F)cc(CCCO)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 111 by LAH reduction of ethyl 3-(3,5-difluoro-4-((3-(4-methoxyphenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)phenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.71 (d, J=8.7 Hz, 2H), 6.99 (d, J=6.6 Hz, 2H), 6.79 (d, J=9.3 Hz, 2H), 5.16 (s, 2H), 3.84 (s, 3H), 3.53 (t, J=6.3 Hz, 2H), 2.61 (t, J=8.1 Hz, 2H), 1.77-1.81 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C21H18F5NO3S, 460.1 (M+H). found 460.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([NH:18]S(C(C)(C)C)=O)[CH2:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15]C)=[O:13])=[C:7]([O:25][CH3:26])[CH:6]=[CH:5][N:4]=1.Cl.O1CCOCC1>CO>[NH2:18][CH:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=1[O:25][CH3:26])[CH2:10][CH:11]([CH3:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(OC)ccnc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of ethyl 4-(2,4-dimethoxypyridin-3-yl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate (0.709 g; 1.83 mmol) in MeOH (15 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.92 ml; 3.67 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 30 min. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate. LC-MS (conditions B): tR=0.45 min. and [M+H]+: 269.33 g/mol; tR=0.47 min. and [M+H]+: 269.33 g/mol (mixture of diastereoisomers).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](N(OC)C)=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1([Mg]Br)[CH2:23][CH2:22]1.C(=O)=O.CC(C)=O>C1COCC1>[CH:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([CH:21]3[CH2:23][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CON(C)C(=O)Cc1ccc(OC2CCCCC2)cc1
Reactant: Br[Mg]C1CC1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(Cc1ccc(OC2CCCCC2)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of 2-(4-cyclohexyloxy-phenyl)-N-methoxy-N-methyl-acetamide (Example 14, 1.31 mmol, 0.36 g) in anhydrous THF (1 mL) at −78° C. was added cyclopropylmagnesium bromide (2 M in diethyl ether, 2.62 mmol, 5.25 mL) dropwise over 5 minutes. The reaction was stirred for 30 minutes at −78° C. The dry ice/acetone bath was replaced with an ice bath and the reaction was stirred for an additional 30 min. The reaction mixture was quenched by addition of saturated ammonium chloride (5 mL) and extracted with ethyl acetate (2×10 mL). The combined ethyl acetate layers were washed with brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 12 g SiO2 column with 6-8% ethyl acetate in hexanes to give 2-(4-cyclohexyloxy-phenyl)-1-cyclopropyl-ethanone (0.24 g).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][C:20]([O:22]CC)=[O:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][C:20]([OH:22])=[O:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CSc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
10 g ethyl S-(4,5-diphenyloxazol-2-yl)-mercaptoacetate dissolved in 30 ml ethanol were mixed with 30 ml 40% NaOH and maintained for 1 hour at room temperature. The sodium salt which separated from the reaction mixture was redissolved by means of addition of 200 ml distilled water. The alkaline solution was slowly poured into 300 ml ice-cooled 15% HCl. The precipitated S-(4,5-diphenyloxazol-2-yl)-mercaptoacetic acid was filtered, washed with water and crystallized from aqueous ethanol to give 7.4 g of a product melting at 137°-139° C (yield = 80.7%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[C:27]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:26]=1)(=O)C.[OH-].[Na+].[Cl-].[NH4+].Cl>O1CCCC1>[C:36]([C:27]1[CH:26]=[C:25]([C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][OH:4])[CH:30]=[CH:29][C:28]=1[N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])([CH3:38])([CH3:39])[CH3:37]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCOC(C)=O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCO)cc1C(C)(C)C
Yield: 51.9 %

Procedure:
1 g (1.9 mmol) of ethyl 4′-(2-acetoxyethoxy)-3″-tert-butyl-4″-diethylamino[1,1′;3′,1″]terphenyl-4-carboxylate is placed in 50 mL of tetrahydrofuran and 19 mL (19 mmol) of 1N sodium hydroxide solution are added. The mixture is stirred at reflux for 12 hours. The yellow solution obtained is poured into saturated ammonium chloride solution, the pH is adjusted to 5-6 with 1N hydrochloric acid solution and the mixture is then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated to dryness. 455 mg of 3″-tert-butyl-4″-diethylamino-4′-(2-hydroxyethoxy)-[1,1′;3′,1″]terphenyl-4-carboxylic acid are obtained in the form of a white solid (yield=52%, m.p.=216° C.)
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C@@H:23]1[C:27]2[NH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:26]=2[C:25](=[O:40])[NH:24]1>>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH3:19])[C:14](=[O:20])[C:13]2[C:8](=[C:9]([C:29]3[NH:28][C:27]4[C@@H:23]([CH3:22])[NH:24][C:25](=[O:40])[C:26]=4[CH:30]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: COCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Product: COCCn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](C)NC4=O)cccc2c1=O
Yield: 38.8 %

Procedure:
This compound (97 mg, 39% yield) as a brown solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-8-iodo-3-(2-methoxyethyl)quinazolin-4(3H)-one (715) (245 mg, 0.61 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (208 mg, 0.79 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br.), 7.90 (2H, m), 7.66 (1H, s), 7.20 (1H, t, J=7.7 Hz), 6.74 (1H, s), 6.51 (1H, s), 4.55 (1H, q, J=6.7 Hz), 4.28 (2H, m), 3.71 (2H, t, J=4.5 Hz), 3.36 (3H, s), 1.49 (9H, s), 1.38 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 410.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][CH3:10]>C1COCC1>[CH3:8][N:9]([CH3:10])[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: Clc1ncccn1
Solvent: C1CCOC1
Product: CN(C)c1ncccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloropyrimidine (5g, 43.65mmol) in dry THF (50ml) is saturated with gaseous dimethylamine. The mixture is stirred at ambient temperature for 1 hour followed by evaporation of solvent. The residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated to leave the product as a brownish oil. Yield 5.07g (94%).