Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:7][GeH:8]([Cl:10])[Cl:9]>>[CH3:3][CH:2]([CH2:4][Ge:8]([Cl:10])([Cl:9])[Cl:7])[C:1]([OH:6])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: Cl[GeH](Cl)Cl
Product: CC(C[Ge](Cl)(Cl)Cl)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
84.7 ml (0.1 mol) of methacrylic acid was added dropwise over 5 minutes to 18 g (0.1 mol) of crude trichlorogermane which had been cooled to 5° C. in an ice bath. The mixture was stirred at the same temperature for one hour and then at room temperature for 1.5 hour. The precipitated crystal was filtered by suction, washed with 10 ml of n-hexane which had been dried over potassium chloride for four times, dried by suction and kept in a desiccator containing phosphorus pentoxide at 65° C. for one hour with reducing the pressure by a vacuum pump which uses potassium hydroxide containing trap to obtain 17.03 g of crystalline 2-methyl-3-(trichlorogermyl) propionic acid:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([O:25]C(C)(C)C)=O)[CH:21]=[CH:22][C:5]=2[NH:4]1.[CH3:30][N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[C:32]1[CH2:40][NH:41][CH3:42].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[CH:19]=[C:20]([C:23]([N:41]([CH3:42])[CH2:40][C:32]3[N:31]([CH3:30])[C:39]4[C:34]([CH:33]=3)=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:25])[CH:21]=[CH:22][C:5]=2[NH:4]1
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Reactant: CNCc1cc2ccccc2n1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(CCc1ccccc1)C(=O)[C@@H](CO)N2
Yield: 88.9 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-hydroxymethyl-3-oxo-4-phenethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.49 g, 1.2 mmole), 1-methyl-2-(methylaminomethyl)indole (0.23 g, 1.4 mmole), Et3N (0.37 mL, 2.62 mmole), HOBt.H2O (0.19 g, 1.4 mmole), and EDC.HCl (0.27 g, 1.4 mmole), the title compound (0.53 g, 82%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 1-3% MeOH/CHCl3): MS (ES) m/e 497.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][OH:29])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C@:10]([CH2:28][O:29][CH3:31])([CH2:11][C:12]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:13]=3[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2

Procedure:
The title compound was prepared by the method of Preparation 2b using (R)-1-(4-fluoro-phenyl)-4a-hydroxymethyl-1,4,4a,5,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthalene-6-carboxylic acid tert-butyl ester and iodomethane. 1H NMR (CDCl3): δ 7.47-7.40 (m, 3H), 7.19-7.12 (m, 2H), 6.32-6.29 (d, 1H, J=2.2 Hz), 4.45-4.30 (d, 1H, J=14 Hz), 4.27-3.92 (bs, 1H), 3.29 (s, 3H), 3.19-3.13 (d, 1H, J=9.1 Hz), 3.09-2.97 (d, 2H, J=16 Hz), 2.92-2.65 (m, 2H), 2.59-2.46 (m, 1H), 2.40-2.20 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[O:10][N:9]=1)=O)C>C(O)C>[OH:5][CH2:6][C:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[O:10][N:9]=1
Reactant: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc(CO)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
Sodium borohydride (610 mg, 16 mmol) was added in portions to a solution of 3-ethoxycarbonyl-5-[N-(tert-butyloxycarbonyl)aminomethyl]isoxazole (Method 73; 1.62 g, 6 mmol) in ethanol (15 ml) at 0° C. under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 4 hours then quenched with saturated aqueous sodium hydrogen carbonate solution. The mixture was extracted with EtOAc and the organics washed with brine then dried (MgSO4). The solvent was removed by evaporation to give the title compound (1.25 g, 91%). NMR (DMSO): 1.38 (s, 9H), 4.21 (d, 2H), 4.44 (s, 2H), 5.40 (br s, 1H), 6.21 (s, 1H), 7.49 (br s, 1H); m/z 229 (MH)+.
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([OH:16])[CH2:14][OH:15])=[CH:9][C:8]=1[F:17].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl>[Si:22]([O:15][CH2:14][C@@H:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([F:17])[CH:9]=1)[OH:16])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: OC[C@H](O)c1ccc(Cl)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccc(Cl)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
Imidazole (13.1 g, 193 mmol) was added to a cold (0° C.) solution of (R)-1-(4-chloro-3-fluorophenyl)ethane-1,2-diol (14.7 g, 77.1 mmol) in DCM (100 mL), followed by TBSCl (12.8 g, 84.8 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then quenched with water (50 mL). The layers were separated, and the organics were dried, filtered and concentrated. The crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (100:1) to give (R)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanol (11.0 g, 47% over two steps). 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 1H), 7.20 (m, 1H), 7.08 (m, 1H), 4.71 (m, 1H), 3.75 (m, 1H), 3.49 (m, 1H), 2.96 (d, J=2.6 Hz, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccccn1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccccn2)nc2cccnc21
Yield: 32.5 %

Procedure:
Solid N-[3-[(2-pyridinylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (21.9 g, 0.069 mole) was heated in glass at 210°-220° C. using a heating mantle for 71/2 minutes. The residue was dissolved in methylene chloride, treated with 25.6 g of charcoal, and filtered through a Celite pad. The filtrate was evaporated to a dark residue, which was taken up in ethyl acetate and filtered to remove an insoluble brown solid. The concentrated ethyl acetate filtrate was applied to a silica gel column (400 g) and eluted with ethyl acetate. The appropriate fractions were combined and evaporated to a solid, which was placed under high vacuum for several hours. The solid residue (6.9 g) was recrystallized from ethanol-water and refrigerated overnight. The crystalline precipitate was filtered, washed with water, and dried under high vacuum at room temperature overnight to give 6.34 g of title compound (31%), mp 109°-111° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](S([O-])(=O)=O)=[CH:6][CH:5]=1.[K+].[NH2-:15].[K+].N>>[NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:15])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(S(=O)(=O)[O-])cc1
Reactant: [NH2-]
Agent: N
Agent: [K+]
Product: NCCc1ccc(N)cc1
Yield: 82.2 %

Procedure:
In a 200-ml autoclave were placed 12 grams (0.05 mole) of anhydrous potassium p-(2-aminoethyl)benzene sulfonate, 6.1 grams (0.11 mole) of potassium amide and 55 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 135° C for 5 hours. The reaction pressure in the autoclave was 115 atm. during the reaction. After the ammonia was removed, 10 ml of water was added to the reaction mixture for hydrolysis. The product was extracted with ether and the ether was distilled off to produce crude 4-(2-aminoethyl)aniline. The recrystallization thereof from ether gave 5.6 grams of 4-(2-aminoethyl)aniline having a melting point of 62° to 63° C and boiling point of 140° to 142° C/12 mm Hg. Yield was 82.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C2=CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C2=CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Yield: 77.8 %

Procedure:
A solution of 1,1-dimethylethyl 4-{4-[3-(methyloxy)-4-nitrophenyl]-3-cyclohexen-1-yl}-1-piperazinecarboxylate (0.75 g, 1.80 mmol, combined batches) was stirred at rt under N2 in 20% TFA in DCM (40 mL) for approximately 2 h. The solution was then concentrated under vacuum. The residue was dissolved in DCM and aqueous (saturated) NaHCO3. The aqueous layer was separated and extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step F (446 mg, 1.40 mmol, 78%) as a light tan solid. MS (ESI): 318 [M+H]+.
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2.[CH2:31]([Mg]Br)[CH3:32]>C1COCC1>[OH:1][CH:2]([CH2:31][CH3:32])[CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([NH:16][CH:17]4[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CC=O)CC4)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)C[C@H]1CCc2sc3ncnc(NC4CCC(NC(=O)OC(C)(C)C)CC4)c3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a 50-mL round-bottom flask, purged and maintained under an inert atmosphere of nitrogen, was added a solution of 26.3 (244 mg, 0.57 mmol, 1.00 equiv) in distilled THF (10 mL) at 0° C. under nitrogen. Then C2H5MgBr (1 M in THF, 2.85 mL, 5.0 equiv) was added dropwise at 0° C. via syringe. The resulting solution was stirred for an additional 2 h at 0° C., quenched with saturated aqueous NH4Cl and extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:5) and purified to give racemic tert-butyl N-(4-[[(3R)-3-(2-hydroxybutyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino]cyclohexyl)carbamate (30.1, 130 mg, 50%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][OH:28])[CH2:22]1>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([CH2:27][OH:28])[CH2:22]3)=[N:12][C:11]1=2)[CH3:14]
Reactant: OCC1CCCNC1
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCCC(CO)C3)nc21

Procedure:
The title compound, m.p. 194°-197° C., was synthesized from 2-chloro-5,11-dihydro-11l-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-piperidinemethanol using procedures analogous to those described above, except that the mixture was heated at 170°-180° C. for 2.5 hrs, and the product was crystallized from ethyl acetate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=C(CBr)c1ccc(-n2ccnc2)nc1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4ccnc4)nc3)cn2c1
Temperature: 100 °C

Procedure:
24.3 mg (corresponding to 0.0876 mmol) of 5-(2-bromoacetyl)-2-(1H-imidazole-1-yl)pyridine and 19.3 mg (corresponding to 0.0876 mmol) of 2-amino-5-iodopyridine were dissolved in 2.0 mL of acetonitrile. The resulting solution was heated under reflux for 1.5 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 2 mL of water and 2 mL of methanol. Then, about 1 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain crude crystals of 6-iodo-2-[2-(1H-imidazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine. The resulting crude crystals were purified by flash silica gel column chromatography (elution solvent: ethyl acetate/methanol=10/1), to obtain 17.7 mg (corresponding to 0.046 mmol) of 6-iodo-2-[2-(1H-imidazole-1-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 3, step 3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][OH:14])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].O>O1CCCC1>[CH2:15]([O:14][CH2:13][CH2:12][N:8]([CH:9]([CH3:10])[CH3:11])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N(CCO)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(CCOCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
A solution of 2-(N-tert-butoxycarbonyl-N-isopropylamino)-ethanol (3.00 g, 14.8 mmol) and benzyl bromide (2.6 ml, 22.1 mmol) in anhydrous tetrahydrofuran (30 ml) was added to a solution of 60% sodium hydride (885 mg, 22.1 mmol) in anhydrous tetrahydrofuran (20 ml) under ice-cooling, and the mixture was stirred at 60° C. for four hours. Water (100 ml) was added to the reaction mixture under ice-cooling, the temperature was returned to room temperature, and the whole was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine (100 ml) and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase: hexane/ethyl acetate=4/1) to give 1.30 g (30%) of the target compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[CH3:20][O-:21].[Na+]>CN(C=O)C.CCOCC>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:5]1[N:6]=[N:7][C:2]([O:21][CH3:20])=[CH:3][C:4]=1[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1cc(Cl)nnc1Nc1ccc(I)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)c(Nc2ccc(I)cc2F)nn1
Temperature: 135 °C

Procedure:
To solid 6-chloro-3-(2-fluoro-4-iodo-phenylamino)-pyridazine-4-carboxylic acid (34 mg, 0.09 mmol) in DMF was added NaOMe (0.43 mmol, 0.5 M in MeOH). The mixture was heated at 135° C. for 3 h. The mixture was diluted with ether and extracted with NaOH (1N). The aqueous layer was acidified by concentrated HCl. The desired product was precipitated and was collected by vacuum filtration. LC/MS [8.08 min; 390 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][C:7]([Cl:13])([NH:15][NH2:16])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NN
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Solvent: CCO
Solvent: O
Product: NNC1(Cl)C=Cc2nc(Cl)cnc2C1

Procedure:
A mixture consisting of 23 g. (0.10 mole) of 2,3,6-trichloroquinoxaline and 11 g. (0.22 mole) of hydrazine hydrate in 500 ml. of ethanol was stirred at room temperature (~20° C.) overnight (~16 hours). The precipitate which formed was separated by filtration and washed with ethanol to ultimately afford 22.2 g. (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p. <250° C. Mass Spectrum: m/e, 228 (P).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]([CH3:33])([CH3:32])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30]>ClCCl>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][CH2:9][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:33])[CH3:32])=[C:12]([N+:29]([O-:31])=[O:30])[CH:13]=[N:14]2)=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)NC(C)(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropyl isocyanate (2.05 mL, 20.9 mmol) was added to a stirred suspension of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine (prepared as described in Part A of Example 45, 6.95 g, 19.0 mmol) in dichloromethane (200 mL) at 0° C. After approximately 30 minutes, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure to afford 8.49 g of N-(2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[C:10]1=S)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Ni]>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27])[CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1=S
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cccc3ccc(O[Si](C)(C)C(C)(C)C)cc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(R)-3-(tert-Butoxycarbonylamino)-1-[7-(tert-butyldimethylsilyloxy) naphthalen-1-yl]-2-thioxopyrrolidine, as described above in Step G, (1.04 g, 2.19 mmol) was dissolved in EtOH (100 mL) and Raney Ni (5 g of a slurry in EtOH) was added. The mixture was stirred at ambient temperature for 18 hours, then an additional portion of Raney Ni (3 g of a slurry in EtOH) was added. After a further 4 hours stirring, the reaction mixture was filtered through a pad of celite, washing with EtOH. The filtrate was concentrated in vacuo to provide the desired product.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH2:11][CH2:12][C:13](=[O:31])[CH2:14][CH2:15][S:16][CH2:17][CH2:18][C:19](=[O:30])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[CH3:29].Cl>C(O)C>[CH3:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[CH2:21][CH2:20][CH:19]([OH:30])[CH2:18][CH2:17][S:16][CH2:15][CH2:14][CH:13]([OH:31])[CH2:12][CH2:11][C:5]1[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=1[CH3:3]
Reactant: Cc1ccc(C)c(CCC(=O)CCSCCC(=O)CCc2cc(C)ccc2C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C)c(CCC(O)CCSCCC(O)CCc2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
1.65 g (43.6 mmol) of sodium borohydride was gradually added to 16.1 g (72.6 mmol) of the (2,5-dimethylphenyl)-3-oxopentylsulfide and 64 ml of ethanol at 0° C., and the mixture was stirred at room temperature for 1 hour. The mixture was poured into ice and an aqueous solution containing 5% hydrochloric acid and extracted with dichloroethane. The extract was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give 16.3 g of (2,5-dimethylphenyl)-3-hydroxypentylsulfide in the form of a colorless transparent oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:11]=1[C:26](OCC)=[O:27]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:26]([C:11]2[CH2:12][N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[C:19]([C:10]=2[OH:9])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:27])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)cn1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Yield: 65.9 %

Procedure:
A solution of 21.98 g of 2-amino-5-bromopyridine and 25.0 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 250 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 20 g of 4 Å molecular sieves. Evaporation of the volatiles afforded a residue which was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent). The resultant solution was degassed and evaporated to yield 23.56 g (66%) of N-(5-bromo-2-pyridyl)-1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxamide, m.p. 153°-154° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1B1OCC(C)(C)CO1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][C:46]=1[C:55]1[CH:60]=[CH:59][N:58]=[N:57][CH:56]=1>O1CCCC1.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:1]([C:3]1[CH:4]=[C:5]([S:17]([N:20]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[O:35][CH3:36])[C:21]2[S:25][N:24]=[CH:23][N:22]=2)(=[O:18])=[O:19])[CH:6]=[CH:7][C:8]=1[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([F:53])([F:54])[F:52])=[CH:47][C:46]=1[C:55]1[CH:60]=[CH:59][N:58]=[N:57][CH:56]=1)#[N:2]
Reactant: FC(F)(F)c1ccc(CBr)c(-c2ccnnc2)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(B3OCC(C)(C)CO3)c(C#N)c2)c(OC)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: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Cc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(C#N)c2)c(OC)c1
Temperature: 65 °C

Procedure:
To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 29, 100 mg, 0.19 mmol) in tetrahydrofuran (2 mL) was added a 2 M aqueous solution of potassium carbonate (270 μL, 0.54 mmol) and 4-[2-(bromomethyl)-5-(trifluoromethyl)phenyl]pyridazine (Preparation 33, 57 mg, 0.18 mmol). The solution was sparged with nitrogen before the addition of tetrakis(triphenylphosphine)palladium (0) (20.8 mg, 0.018 mmol). The reaction mixture was heated at 65° C. for 6 hours. The reaction mixture was cooled to ambient temperature and partitioned between a saturated aqueous solution of ammonium chloride (5 mL) and ethyl acetate (2×10 mL). A saturated aqueous solution of sodium chloride was added to aid the separation. The combined organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a brown oil. The material was purified by silica gel column chromatography (ISCO™ companion, 12 g column, 0-30% ethyl acetate in heptane gradient elution). Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a foam.