Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH:17]=1)[CH:15]=[O:16]>C1COCC1.O1CCOCC1.O=[Mn]=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([C:15](=[O:16])[C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:17]=1
Reactant: CC(C)Oc1ccc(Br)cc1C=O
Reactant: C#Cc1ccccc1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Br)cc1C(=O)C#Cc1ccccc1
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
To a stirred solution of phenyl-acetylene (0.27 ml, 2.46 mmol) in anhydrous THF (3 ml) 2M iPrMgC1 in THF (1.25 ml) was added drop wise at 0° C. under N2. After stirring for 15 min, the solution of product of Step A (0.5 g, 2.06 mmol) in anhydrous THF (2 ml) was added drop wise and the mixture was stirred for 1 h at room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (50 ml). The organic layer was washed with H2O, dried over MgSO4. and filtered. The filtrate was evaporated to dryness to give a creamy paste (0.59 g; 83%). [1H-NMR (CDCl3) 7.68 (d, 1H, J=2.49 Hz); 7.46-7.43 (m, 2H); 7.36 (dd, 1H, J=8.75, 2.54 Hz); 7.32-7.28 (m, 3H); 6.79 (d, 1H, J=6.77 Hz); 5.79 (d, 1H, J=5.23 Hz); 4.64-4.58 (m, 1H); 3.13 (d, 1H, J=5.91 Hz); 1.37 (d, 6H)]. This was dissolved in dioxane (10 ml) and MnO2 (1 g) was added to it. The resulting suspension was stirred for 6 h at reflux, then filtered through Celite and the solvent was evaporated to dryness to give the title compound (0.54 g, 76.5%), as light yellow paste. 1H-NMR (CDCl3) 8.00 (d, 1H, J=2.61 Hz); 7.61-7.52 (m, 3H); 7.44-7.35 (m, 3H); 6.88 (d, 1H, J=8.91 Hz); 4.68-4.60 (m, 1H); 1.36 (d, 6H).
Reaction SMILES: [SH:1][CH:2]1[N:5]([C:6](=[C:20]([OH:23])[CH2:21]Br)[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C:4](=[O:24])[CH:3]1[NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CO>[OH:23][C:20]1[CH2:21][S:1][C@@H:2]2[CH:3]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:4](=[O:24])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=C(O)CBr)C1S
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of p-nitrobenzyl α-[4-mercapto-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)acetate (70 mg) prepared by the method of Example 4-III (2) in a mixture of methylene chloride (2 ml) and methanol (2 ml) is stirred for 3 hours at room temperature. The reaction mixture is poured into ice water, and is extracted with methylene chloride. The extract solution is washed with water, dried over magnesium sulfate, and evaporated to give p-nitrobenzyl 3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate (42 mg), identical with the product of Example 4(3). Yield: 70%.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[NH:18][C:19]1[NH:20][CH2:21][CH2:22][N:23]=1>O1CCCC1>[C:1]([N:23]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:18][C:12]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=1[Cl:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: O=C(O)c1cccnc1
Solvent: C1CCOC1
Product: O=C(c1cccnc1)N1CCN=C1Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48.1 %

Procedure:
5.5 g (44.7 millimoles) of nicotinic acid are dissolved in 800 ml of absolute tetrahydrofuran, 7.3 g (45 millimoles) of N,N'-carbonyldiimidazole are added and the mixture is stirred for 45 minutes at room temperature. A solution of 10.3 g (44.7 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline in 200 ml of absolute tetrahydrofuran is then added dropwise, with continued stirring, and the mixture is left to stand overnight at room temperature. Thereafter, the reaction solution is freed from solvent on a rotary evaporator, 200 ml of an 0.5% strength sodium bicarbonate solution are added to the residue, and the product which precipitates is filtered off and washed with water. After drying, the crude product is recrystallized from isopropanol. 7.2 g of 1-nicotinoyl-2-(2',6'-dichlorophenylamino)-2-imidazoline, melting point 173°-174° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]#[N:34])=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:22][CH:23]=1)#[N:34]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccccc4C#N)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-2-cyanobiphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.93 (dd, J=7.0, 2.0 Hz, 2H), 7.75 (dd, J=7.7, 1.0 Hz, 1H), 7.64 (dt, J=1.3, 7.7 Hz, 1H), 7.42-7.50 (m, 4H), 7.31 (d, J=8.3 Hz, 2H), 7.07 (dd, J=7.1, 1.9 Hz, 2H), 4.00 (A of AB, J=13.7 Hz, 1H), 3.93 (s, 3H), 3.42 (B of AB, J=13.7 Hz, 1H) MS (m/e): 477.3 (M−H)+. Anal: Calc for C24H18N2O5S2.0.167 C3H9NO: 59.92% C, 4.00% H, 6.18% N; Found: 59.60% C, 4.04% H, 5.99% N.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)[CH:24]=1>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:2]2[CH2:3][CH:4]3[CH2:8][N:7]([C:27]([C:26]4[CH:30]=[CH:31][C:23]([F:22])=[CH:24][C:25]=4[N:32]4[N:36]=[CH:35][CH:34]=[N:33]4)=[O:28])[CH2:6][CH:5]3[CH2:1]2)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Reactant: CN(C)c1nc(N2CC3CNCC3C2)cc(C(F)(F)F)n1
Product: CN(C)c1nc(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 36 and Intermediate 4. MS (ESI): mass calculated for C22H22F4N8O, 490.46; m/z found 490.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.84-7.64 (m, 3H), 7.45-7.36 (m, 1H), 7.20-7.07 (m, 1H), 5.87 (br s, 1H), 4.04-2.79 (m, 16H).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4)c3c2s1
Yield: 89 %

Procedure:
Prepared from VII and 4-chloroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 89%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2850, 2229, 1643, 1609, 1583, 1550, 1491, 1480, 1457, 1377, 1355, 1307, 1270, 1214, 1164, 1130, 1092, 1010, 980, 831; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=8.7 Hz), 8.18 (s, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.38 (m, 2H), 7.04 (m, 2H); HRMS calcd for C16H9N5SCl (M+H+): 338.0267, found 338.0274.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][NH2:14].[BH4-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:14][CH3:13])=[CH:3]1
Reactant: CN
Reactant: Cn1cc(C=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylindole-3-carboxaldehyde (10.0 g, 62.8 mmole) in MeOH (100 mL) was added a solution of 2.0 M CH3NH2 in MeOH (126 mL, 252.0 mmole). The reaction was stirred at RT for 2 hrs, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (300 mL), and NaBH4 (2-38 g, 62.8 mmole) was added. After 2 hrs the reaction was concentrated to a slurry and dissolved in 1.0 N NaOH (75 mL). The aqueous solution was extracted with Et2O (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying in high vacuum left the title compound (10.1 g, 92%) as a faintly yellow oil: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][O:28][C:33]3[N:32]=[CH:31][C:40]4[C:35]([CH:34]=3)=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: Clc1ccc2ccccc2n1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3cc4ccccc4cn3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 86.3 %

Procedure:
Step 3C 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (700 mg, 1.68 mmol, 1 equiv), 2-chloroquinoline (1.1 g, 6.7 mmol, 4 equiv) were dissolved in DMF (20 mL) and added with and NaH (202 mg,60% in oil, 5.04 mmol, 3 equiv). The mixture was heat to 100° C. for 2 hrs. After cooling to room temperature, the reaction mixture was quenched with sat. NH4Cl (aq). After stirring for 0.5 h, solid precipitated from the mixture. Solid was collected by filtration and washed with water and dried overnight to produce 793 mg of 2-[4′-(Isoquinolin-3-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 87% yield.
Reaction SMILES: [NH2:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][NH:1][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: N[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Temperature: 25 °C

Procedure:
(1S,2R)-2-amino-1,2-diphenylethanol (3.15 g) was dissolved in dichloromethane (45 ml) and stirred at room temperature. Ethyl bromoacetate (3.0 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (2.31 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (3.41 g, 77%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure. Yield 3.25 g (73%); mp 126.5°-127° C.; [α]D22 -2.5° (c 1.01, EtoH). IR and 1H-NMR spectra, and Rf value of the product are completely identical with those of (1R,2S)-form mentioned in Example 1.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:28]1[CH2:29][CH2:30][C:25]([F:31])([F:24])[CH2:26][CH2:27]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC1(F)CCNCC1
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Product: O=C(O)c1c(N2CCC(F)(F)CC2)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and 4,4-difluoro-piperidine. Yellow foam. MS (ESI): 437.1 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:10]1[CH:22]=[CH:21][C:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[CH:12][CH:11]=1>C1COCC1>[C:1]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])=[CH:12][CH:11]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCCC1Cc1ccc(I)cc1
Reactant: C#CCCCCCC
Solvent: C1CCOC1
Product: CCCCCCC#Cc1ccc(CC2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.1 g (10 mmol) of 1-Octyne was added to a flame dried 25 mL flask charged with a 10 mL THF solution of 1.49 g (5 mmol) of 2-(4′-iodobenzyl)cyclopentanone (3). After degassing for 30 minutes, 2 mL triethylamine, 5 mg of CuI and 10 mg of Pd(PPh3)4 were added under N2 protection. The reaction was stirred at room temperature for 6 hrs, then the solvent removed in vacuo and residue chromotographed with chloroform eluent to give 1.25 g (93%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:9][C:10]=1[CH3:11])[CH3:5].C1C(=O)N([Br:27])C(=O)C1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[S:9][C:10]=1[CH2:11][Br:27])[CH3:5]
Reactant: COC(=O)C(C)c1nc(-c2ccc(Cl)cc2)sc1C
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)C(C)c1nc(-c2ccc(Cl)cc2)sc1CBr

Procedure:
A mixture of methyl-2-(5-methyl-2-(4-chlorophenyl)thiazol-4-yl)propionate (Compound No. 178) (0.5 g, 1.7 mmol), NBS (0.33 g 1.87 mmol), benzoyl perodide (cat.), were irradiated (UV) for 2 hours. The reaction mixture was cooled, filtered, and the filtrate concentrated under reduced pressure. The residue on trituration with hexane gave the product (0.45 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.4) (0.21 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.14 g, 66%). MS (ISP) 427.0 [(M+H)+]; mp 171° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCN(C2CCNCC2)CCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-piperidin-4-yl-[1,4]diazepan-5-one (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3241.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[C:7]=1[Cl:8]
Reactant: CN1CCNCC1
Reactant: Clc1cnnc(Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN1CCN(c2cnnc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
3,4,5-Trichloropyridazine (3 g, 16.36 mmol) was dissolved in dry NMP (18 mL) and cooled in an ice-bath. DIPEA (2.326 g, 3.135 mL, 18 mmol) was added, followed, dropwise, by 1-methylpiperazine (1.721 g, 1.906 mL, 17.18 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated under reduced pressure to give an brown solid which was partitioned between 10% MeOH in DCM and saturated NaHCO3. The aqueous layer was extracted with further 10% MeOH in DCM (5×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a brown oil which was purified by column chromatography (7.5% MeOH in DCM, ˜300 mL silica, loaded in DCM) to provide 3,4-dichloro-5-(4-methylpiperazin-1-yl)pyridazine as a light yellow solid (2.36 g, 58% Yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[NH:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=2)=[O:23])=[CH:4][CH2:3]1.[C:32]([O:36]C)(=[O:35])[CH2:33]O.C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[C:29]([C:26]1[NH:25][C:24]([C:22]([NH:21][C:9]2[CH:10]=[CH:11][C:12]([C:14]3([O:20][CH2:33][C:32]([OH:36])=[O:35])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:8]=2[C:5]2[CH2:6][CH2:7][C:2]([CH3:31])([CH3:1])[CH2:3][CH:4]=2)=[O:23])=[N:28][CH:27]=1)#[N:30]
Reactant: COC(=O)CO
Reactant: CC1(C)CC=C(c2cc(C3(O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC=C(c2cc(C3(OCC(=O)O)CCOCC3)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
To a suspension of 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(4-hydroxy-tetrahydro-pyran-4-yl)-phenyl]-amide (48.0 mg, 0.114 mmol)(prepared in Example 1, step (h)) in 1 mL of DCM was added methyl glycolate (0.215 mL, 2.78 mmol), TFA (0.036 mL, 0.464 mmol), and the mixture was stirred for 8 h at RT. The mixture was concentrated and the methyl ester of the title compound was eluted from a 10-g SPE column with 50% EtOAc/hexanes. The resulting ester was dissolved in 1 mL of MeOH, 2N KOH (0.30 mL, 0.60 mmol) was added and the mixture stirred for 8 h at RT. The title compound was purified by RP-HPLC on a C18 column eluting with a linear gradient of 30-60% CH3CN in 0.1% TFA/H2O over 12 min to give 13 mg (30%) of a white solid. 1H-NMR (400 MHz, CD3OD): δ 8.34 (d, J=8.6 Hz, 1H), 7.85 (s, 1H), 7.60 (s, 1H), 7.37 (dd, J=8.6, 2.2 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 5.79 (m, 1H), 4.03-3.94 (m, 2H), 3.88-3.80 (m, 2H), 3.72 (s, 2H), 2.35-2.27 (m, 2H), 2.13-2.06 (m, 4H), 1.60 (t, J=6.3 Hz, 2H), 1.11 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30N4O5, 477.2 (M−H). found 477.2.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:16][CH2:17][NH2:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:18][CH2:17][CH2:16][C:8]2[NH:9][C:10]3[C:15]([C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:23])[CH2:21][CH2:20]1
Reactant: NCCc1[nH]c2ccccc2c1-c1ccccc1
Reactant: O=C(Cl)C1CC1
Product: O=C(NCCc1[nH]c2ccccc2c1-c1ccccc1)C1CC1

Procedure:
3-Phenyl-1H-indol-2-ethanamine are reacted with cyclopropanecarboxylic acid chloride to give N-cyclopropylcarbonyl-3-phenyl-1H-indol-2-ethanamine, which is reduced with lithium aluminium hydride to N-cyclopropylmethyl-3-phenyl-1H-indol-2-ethanamine, which is reacted with chloracetyl chloride to give 2-chloro-N-cyclopropylmethyl-N-[2-(3-phenyl1H-indol-2-yl)ethyl]acetamide, m.p. 104°-106° (from ethanol/pentane).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4](Cl)[N:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16].O>O1CCCC1>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([NH:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11])[N:3]=1
Reactant: COCCCN
Reactant: Nc1nc(Cl)nc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: O
Product: COCCCNc1nc(N)c(Cl)c(Cl)n1
Reaction time: 6 h

Procedure:
1,850 g (9.31 moles) of 4-amino-2,5,6-trichloropyrimidine are dissolved in 4 liters of tetrahydrofuran. 1,659 g (18.62 moles) of 3-methoxypropylamine are added dropwise thereto over a period of 6 hours. The reaction mixture is heated for five hours at the boil, cooled and stirred into 20 liters of water. The resulting solid is filtered off, dried, stirred with 7 liters of methylene chloride and again filtered off. After the solid thus obtained has been twice recrystallised from toluene, 743 g (31.8% of theory) of the desired pyrimidine, melting point 114° C., are obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccccc1C(F)(F)F)C(O)c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(2-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (434 mg, 87%).
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CI.[K].[CH3:17]C(C)([O-])C>CN(C)C=O>[C:1]([C:4]1[C:9]2[N:10]([CH3:17])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc2oc(=O)[nH]c12
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)c1cccc2oc(=O)n(C)c12

Procedure:
Prepared by reacting 4-acetyl-3H-benzoxazol-2-one with methyl iodide in the presence of potassium-tert.-butoxide in N,N-dimethylformamide at ambient temperature.