Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH:6]([CH3:10])[C:7](Br)=[O:8].[Cl:11][C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1.Cl>ClCCCl>[Br:5][CH:6]([CH3:10])[C:7]([C:17]1[CH:16]=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=1[Cl:11])=[O:8]
Reactant: CC(Br)C(=O)Br
Reactant: COc1cccc(Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)C(C)Br)c(Cl)c1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) stirring suspension of aluminum chloride (10.89 g, 82 mmol) in DCE (700 ml) is added 2-bromopropionyl bromide (8.66 ml, 82 mmol) followed by 3-chloroanisol (10 ml, 82 mmol) dropwise (rapidly) maintaining the temperature below 5° C. The reaction mixture is stirred at 0° C. for 10 min and RT for 3 hours. The mixture is poured into ice/water (1000 ml) containing 90 ml of 5M HCl. The organic phase is separated and the aqueous portion is washed with DCM (500 ml). The organic extracts are combined, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 2.5% incraesing to 5% TBME/Hex increasing up to 5% affords the title product. MS: m/z 278.9 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:8]#[N:9])=[CH:4][CH:3]=1.C1C(=O)N([Br:26])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:26][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:8]#[N:9])=[CH:17][CH:18]=1
Reactant: Cc1ccc(OC(C#N)c2ccccc2Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(Oc1ccc(CBr)cc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a CCl4 solution (5 mL) of the product (0.200 g) of Step B was added NBS (0.132 g, 0.95 eq) and a catalytic amount of AIBN. The reaction mixture was refluxed overnight. TLC indicated clean conversion to product, and the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified on a silica gel flash chromatography column (120×30 mm) eluted with 5% ethyl acetate in hexane to afford 0.178 g (72%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)C(C)C)(C)C.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH2:15][CH3:16])=[O:13])=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N)cc1F
Temperature: 110 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
4-Bromo-3-fluoroaniline (13.3 g, 70.0 mmol), ethyl acrylate (9.48 mL, 87.5 mmol) and tris(2-methylphenyl)phosphine (8.52 g, 28.0 mmol) were dissolved in N,N-diisopropylethylamine (50 mL) and N,N-dimethylformamide (50 mL), palladium(II) acetate (0.786 g, 3.50 mmol) was added, and the mixture was stirred under an argon atmosphere at 110° C. for 5 hr. After cooling the reaction mixture, the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the insoluble material was removed by filtering through celite. The organic layer in the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane) to give the title compound (14.0 g, yield 96%). A part thereof was recrystallized to give yellow prism crystals.
Reaction SMILES: [CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[H-].[Na+].Br.Cl[C:12]1[CH:13]=[C:14]([CH3:22])[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=1.O>CN(C=O)C>[CH3:22][C:14]1[C:15]2[N:16]([C:18]([NH2:21])=[N:19][N:20]=2)[N:17]=[C:12]([O:7][CH2:6][C:2]2([CH3:1])[CH2:5][O:4][CH2:3]2)[CH:13]=1
Reactant: CC1(CO)COC1
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCC2(C)COC2)nn2c(N)nnc12
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
(3-Methyloxetan-3-yl)methanol (1.74 g) was initially charged in DMF (30 ml), admixed under argon with sodium hydride (408 mg) and stirred at 45° C. for 0.5 h. Subsequently, 6-chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g) was dissolved in DMF (30 ml) and one equivalent of the alkoxide solution (10 ml) was added. After stirring at 45° C. for 30 min, a further 0.5 equivalent of alkoxide solution was added, followed by 0.5 eq. each after a further 30 and 60 min. Then the mixture was admixed with water, and the reaction mixture was dried and purified using silica gel (80 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 758 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21](O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O=S(Cl)[Cl:27]>>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21]([Cl:27])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)Cl)C1c1cccc([N+](=O)[O-])c1

Procedure:
Compounds of formula 1 may also be prepared by the following variation of Scheme IV, especially where optically active compounds are desired. A suitable dihydropyridine derivative acid is prepared and the optical isomers separated (where desired) following the procedure set forth by T. Shibanuma, et al., Chem. Pharm. Bull., 28, 2809-2812 (1980). For example, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is N-protected, and subsequently resolved with an optically active amine, e.g., cinchonine, to prepare (+)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (12+) and (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (after deprotection). The resolved dihydropyridine acid derivative is then treated with SOCl2 in a suitable solvent, e.g., dichloromethane, to produce a dihydropyridine acyl chloride for condensation with an intermediate of the formula X--A--OH, where X is halo. For example, (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is reacted with SOCl2 to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-chlorocarbonyl-1,4-dihydropyridine, which is then reacted 3-bromopropanol to give the 3-bromopropoxy carbonyl derivative, which is then reacted with 4-(2-tetrahydropyran- 2-yloxyethyl)phenol (10) in CH2Cl2 with triethylamine to generate (S,RS)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (1+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[C:16]([CH3:18])[CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: Cc1cnn(-c2nc(N)nc(S(C)=O)c2C#N)c1
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cnn(-c2nc(N)nc(SCCc3ccccn3)c2C#N)c1

Procedure:
From 2-amino-4-methanesulfinyl-6-(4-methyl-pyrazol-1-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:37][C:36]5[CH:39]=[CH:40][C:33]([O:32][C:31]([F:30])([F:41])[F:42])=[CH:34][CH:35]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCNC[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.9 %

Procedure:
(8S,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (45 mg, 0.139 mmol, prepared as described in Example 46, Part H) was suspended in dichloromethane (1.5 mL) in a 4-mL scintillation vial. Triethylamine (28.0 mg, 0.277 mmol) was added followed by the addition of 4-(trifluoromethoxy)benzaldehyde (34.2 mg, 0.180 mmol) as a solution in dichloromethane (0.2 mL). The resulting solution was stirred at room temperature for 15 minutes, at which point sodium triacetoxyborohydride (70.5 mg, 0.333 mmol) was added as a neat solid in one portion, and the resulting suspension was stirred at room temperature for an additional 4 hours. The suspension was loaded directly onto a 4 g silica column and eluted with ethyl acetate (flow rate=18 mL/minute) over 15 minutes to give the title compound as a colorless oil (34 mg, 53%). 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=1.2 Hz, 1H), 7.92 (d, J=1.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.41 (t, J=3.9 Hz, 1H), 4.18 (dd, J=16.4, 9.4 Hz, 1H), 4.02 (dd, J=13.7, 2.0 Hz, 1H), 3.69-3.45 (m, 3H), 2.94 (d, J=12.5 Hz, 2H), 2.81 (d, J=12.0 Hz, 1H), 2.60 (dd, J=14.8, 6.9 Hz, 1H), 2.50-2.34 (m, 2H), 2.15 (dd, J=12.8, 9.3 Hz, 1H), 1.98 (tt, J=7.9, 5.1 Hz, 1H), 1.86 (ddd, J=14.4, 10.4, 4.4 Hz, 1H), 1.02-0.79 (m, 4H); MS (ESI+) m/z 463.1 (M+H)+; [α]D24.1=−0.04 (c=0.23, CH3OH).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[CH2:34][CH2:33][CH2:32][NH:31][C:30]2=[O:35])[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:17]1([CH2:16][N:31]2[CH2:32][CH2:33][CH2:34][N:29]([C:21]3[S:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]([CH3:18])[N:20]=3)[C:30]2=[O:35])[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1sc(N2CCCNC2=O)nc1C
Reactant: BrCC1CC1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCCN(CC3CC3)C2=O)nc1C

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with (bromomethyl)cyclopropane to react with ethyl 4-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 324.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([S:28]([NH:14][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:9]([C:8]3[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)(=[O:30])=[O:29])[CH2:27][CH2:26]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1ccccc1
Product: COc1ncccc1-c1cc(C(=O)NS(=O)(=O)C2CC2)ccc1Oc1ccccc1
Yield: 17 %

Procedure:
Prepared according to Example 5 with 3-(2-methoxypyridin-3-yl)-4-phenoxybenzamide (Preparation 19, 0.030 g, 0.09 mmol) and cyclopropylsulfonyl chloride (0.030 g, 0.21 mmol). The product was purified by preparative HPLC to afford the title compound as a white solid (6.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C(NC(C)C)(C)C.[Li].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1>[Cl:31][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)CCC(Cl)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-Methoxy-3,4-dihydro-2H-naphthalen-1-one (5.0 g, 28.37 mmol) in THF (25 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropyl amine in THF (25 ml; prepared from 4.0 ml of diisopropylamine (28.37 mmol) and 17.7 ml of 1.6 M n-BuLi in hexane (28.37 mmol)). After 30 minutes at −78° C., a solution of para-tolylsulfonyl chloride (5.41 g, 28.37 mmol) in THF (25 ml) is added during 20 minutes. The dry ice cooling bath is removed, and the reaction mixture is allowed to reach RT. After 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NH4Cl (100 ml) is added, and the mixture is stirred at RT for 15 minutes. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 920:80 to 880:120) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.54-2.63 (m, 1H), 2.68-2.75 (m, 1H), 3.04-3.12 (m, 1H), 3.38-3.46 (m, 1H), 4.02 (s, 3H); 4.72-4.76 (m, 1H), 6.87 (s, 1H), 7.00-7.04 (m, 1H), 8.22 (d, J=10 Hz, 1H). ES+-MS: 279.1, 280.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:21](OC(C)(C)C)(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:21](=[O:26])[CH2:22][C:23](=[O:24])[CH3:25])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give the title compound as yellow foam. MS (ESI): m/z=406.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])=[C:4]([CH3:15])[C:3]=1[CH3:16].[Mg].C1OC1.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:23][CH2:22][O:21][CH2:25][CH3:24])=[C:3]([CH3:16])[C:4]=1[CH3:15]
Reactant: COC(COc1ccc(Br)c(C)c1C)OC
Reactant: C1CCOC1
Agent: [Mg]
Solvent: C1CO1
Product: CCOCCc1ccc(OCC(OC)OC)c(C)c1C
Reaction time: 2 h

Procedure:
Grignard reaction was carried out in conventional manner from 5.0 g of 4-bromo-1-(2,2-dimethoxyethoxy)-2,3dimethylbenzene and 0.5 g of magnesium in 30 ml of tetrahydrofuran, and then 1.0 g of ethylene oxide was blown into the reaction mixture at 50° C. Further, the mixture was stirred at the same temperature for 2 hours. Tetrahydrofuran was removed under reduced pressure, and 50 ml of toluene and 50 ml of 1 N hydrochloric acid were added. The organic layer separated was washed with water, and then 5 ml of 20% sodium hydroxide, 4.0 g of diethylsulfate and 0.3 g of tetrabutylammonium chloride were added, followed by heating and stirring at 40° C. for 5 hours. After cooling, the toluene layer was washed with water, dried and then concentrated under reduced pressure The residual oil was purified by column chromatography (Wako Gel C-200, eluant: n-hexane ethyl acetate=10:1) to obtain 3.5 g of the title product.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:27]([NH2:32])([CH2:30][CH3:31])([CH3:29])[CH3:28].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:32][C:27]([CH3:29])([CH3:28])[CH2:30][CH3:31])#[N:24]
Reactant: CCC(C)(C)N
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C)(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 49 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.78 mmol, 290 mg), tert-amylamine (0.85 mmol, 0.100 ml) and triethylamine (0.85 mmol, 0.119 ml) in acetonitrile (2 ml) was stirred for 25 h at 75° C. followed by work-up as described in EXAMPLE 5, b) to give the title compound (140 mg, 46%) as white crystals. Mp 149-150° C.; EI SP/MS: 366 (M+); 1H-NMR (CDCl3): δ 0.85 (t, 3H),1.35 (s, 6H), 1.75 (q, 2H), 4.65 (br s,1H), 7.70 (br s, 3H), 8.95 ppm (br s, 1H); MA calc for C15H16F6N4. 0.15 H2O: C, 49.37%; H, 4.57%; N, 14.76%. Found: C, 49.72%; H, 4.56%; N, 14.76%.
Reaction SMILES: Cl.CN([CH2:5][C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)C.[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:18]=1[NH2:19])([CH3:16])[CH3:15]>C(O)CO>[NH2:19][C:18]1[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][C:22]([CH2:5][C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)=[CH:23][C:17]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CN(C)Cc1c[nH]c(=O)[nH]c1=O
Agent: Cl
Solvent: OCCO
Product: CC(C)c1cc(Cc2c[nH]c(=O)[nH]c2=O)cc(C(C)C)c1N

Procedure:
A mixture of 5-dimethylaminomethyluracil hydrochloride (10.28 g, 50.0 mmol) and 2,6-diisopropylaniline (10.64 g, 60.0 mmol) in ethylene glycol (75 mL) was heated for 41/2 hours at 134°-137° C. After cooling, the title compound was filtered, washed with ethanol, and dried (5.55 g, 37%). A second crop was obtained from the mother liquor upon standing (3.24 g, 21.5%). The two crops were combined and recrystallized from methanol to give the purified title compound (5.84 g, 38.8%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10].C(=O)=O>CO>[CH3:8][S@:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:10]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)=O)cc3)nc2)CC1
Agent: O=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc([S@@](C)=O)cc3)nc2)CC1
Yield: 34.4 %

Procedure:
The racemic sulfoxide 1-methylethyl 4-[({6-[4-(methylsulfinyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (Example 173, 370 mg) was subjected to Chiral HPLC [column: Chiralpak AS-H, column mobile phase: 65% CO2: 35% MeOH (1 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separation to give two (R and S) enantiomers. The title compound (100 mg) was isolated as a white solid with Tr of 3.73 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([Cl:13])=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(F)(F)F
Yield: 57 %

Procedure:
Method 5 General Experimental: 4,4,4-Trifluorobutyric acid (70.0 mmol, 10.0 g) in CH2Cl2 (190 ml) was treated with oxalyl chloride (140 mmol, 12.3 ml) and DMF (1 drop), then heated to reflux for 1 h. Solvent and excess oxalyl chloride were removed from the volatile product by simple distillation of the reaction mixture at atmospheric pressure to provide crude 4,4,4-trifluorobutyric acid chloride (6.4 g). 1H NMR (CDCl3) δ 3.20 (2H, t, J=7.2), 2.65-2.45 (2H, m).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[N:16]([C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[CH2:17][CH:18]([C:19](=[O:31])[NH:20][CH:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][CH2:22]3)[CH:12]12)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:21]1([NH:20][C:19]([CH:18]2[CH2:17][N:16]([C:32]([CH:34]3[CH2:35][CH2:36]3)=[O:33])[CH:13]3[CH2:14][CH2:15][N:11]([C:9](=[O:10])[CH:8]([NH2:7])[CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:12]23)=[O:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 46 (430 mg, 0.72 mmol) in DCM (10 mL) was cooled to 0° C. and treated with TFA (4 mL).). After 2 h, the solution was concentrated, diluted with DCM and washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 47 (332 mg) as a white foam that was used without further purification. Mass spectrum, m/z [493.7] (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH2:18][S:19]([NH2:22])(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:19]([CH2:18][CH2:17][NH:16][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=1)=[O:14])(=[O:21])(=[O:20])[NH2:22]
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Reactant: NCCS(N)(=O)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)CCNC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride (1.51 mmol) and 2-amino-ethanesulfonic acid amide (1.51 mmol) in DCM (15 mL) is added diisopropylethylamine (4.53 mmol). The mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is washed with water and DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid (2-sulfamoyl-ethyl)-amide as a solid. MS: 307 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 3.25 (q, 2H), 3.67 (m, 2H), 6.93 (s, N—H), 7.47-7.60 (m, 3H), 8.36-8.48 (m, 2H), 8.92-9.15 (m, N—H), 9.16-9.36 (m, 2H); IC50=55 nM.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:24].[Na+]>C1COCC1.C(OCC)C>[OH:24][CH2:3][CH2:2][CH2:1][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1
Reactant: C=CCn1cc(C=O)c2ccccc21
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cn(CCCO)c2ccccc12

Procedure:
In a 10 mL round-bottom flask, 1-Allyl-1H-indole-3-carbaldehyde (169 mg, 0.91 mmol) is dissolved in 0.5 mL of anhydrous THF. To this solution is added 0.5 M of 9-BBN in THF (2 mL, 1.0 mmol). The reaction is allowed to stir at room temperature for 1 hr, whereupon a 1M solution of NaOH (2.5 mL) is added. The organic layer is diluted with 10 mL of diethyl ether and the aqueous layer is removed. The organic layer is washed 3×10 mL with 1M NaOH, followed by 2×10 mL water and 2×10 mL saturated NaCl solutions. The organic layer is then dried over Na2SO4 and the solvent is removed under reduced pressure to afford 1-(3-hydroxy-propyl)-1H-indole-3-carbaldehyde.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(N(CC)CC)C>CN(C)C=O>[O:4]1[CH2:5][CH2:6][N:1]([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1csc(Cl)n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(N2CCOCC2)n1

Procedure:
The reaction described in Preparation 26 was repeated, but using 1.4 g of morpholine, 3 g of ethyl 2-chlorothiazole-4-carboxylate. 3 g of triethylamine and 12 ml of dimethylformamide, giving the title compound as colorless needles.