Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:66]2[C:73]([O:74][CH3:75])=[CH:72][C:69]([CH:70]=[O:71])=[CH:68][C:67]=2[O:76][CH3:77])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[BH4-].[Na+]>C1COCC1>[CH3:75][O:74][C:73]1[CH:72]=[C:69]([CH:68]=[C:67]([O:76][CH3:77])[C:66]=1[O:65][CH2:64][CH:22]1[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]1)[CH2:70][OH:71]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2c(OC)cc(C=O)cc2OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2c(OC)cc(CO)cc2OC)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 40 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
4-[3′,4′,5′-Tris(octadecyloxy)cyclohexylmethyloxy]-3,5-dimethoxybenzaldehyde (73 mg, 0.07 mmol) was dissolved in THF (2 ml), 4 equivalents of sodium borohydride was added, and the mixture was stirred at 40° C. for 3 hr. The solvent was evaporated, and chloroform was added. The mixture was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate solution and saturated brine. The solvent of the organic layer was evaporated, and acetonitrile was added. The precipitate was collected by filtration and dried to give 3,5-dimethoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzyl alcohol (70 mg, 0.06 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([NH2:32])[CH:26]=[CH:25]2.C([O-])(=O)C.[K+].CCO.O>>[NH2:32][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[C:22]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4]([O:3][CH2:1][CH3:2])=[O:20])[CH:23]=2)[N:28]=1
Reactant: Nc1ccc2cc(Br)ccc2n1
Reactant: CCOC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc2nc(N)ccc2c1
Temperature: 85 °C
Reaction time: 72 h

Procedure:
To a microwave reaction vessel was added ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.7 g, 13 mmol), 6-bromoquinolin-2-amine (2.0 g, 9.0 mmol), PdCl2(PPh(t-Bu)2)2 (0.084 g, 0.13 mmol), potassium acetate (1.8 g, 18 mmol), EtOH (9.9 ml, 170 mmol) and water (2.4 ml, 134 mmol). The reaction mixture was heated at 85° C. for 8 h, and was then partitioned between EtOAc and water. The organic layer was washed with water and brine and allowed to stand for 72 h. The supernatant was decanted from the resulting precipitate and the precipitate was dried in vacuo to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 2 6-(2-Ethoxyphenyl)quinolin-2-amine (1.0 g, 3.8 mmol) was taken up in THF and then 5N NaOH was added and the solution was stirred for 72 h. DCM was added and the solid was filtered to give ethyl 2-(2-aminoquinolin-6-yl)benzoate. Step 3 A solution of 2-(2-aminoquinolin-6-yl)benzoic acid (50 mg, 0.19 mmol), 4-fluoropiperidine (25 mg, 0.24 mmol), HATU (91 mg, 0.24 mmol), DIEA (100 uL, 0.57 mmol), and DMF (1 mL) was heated in a shaker oven at 60° C. for 1 h. The resulting solution was purified by HPLC (CH3CN/water modified with 0.1% TFA) to give (2-(2-aminoquinolin-6-yl)phenyl)(4-fluoropiperidin-1-yl)methanone. MS (ESI, pos. ion) m/z: 350 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([NH:16][CH2:17][C:18]([O:20]C)=[O:19])=[O:15].CO.[C:24]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:24][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: COC(=O)CNC(=O)c1c(O)c2ccccc2n(C)c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(=O)NCC(=O)O)c(=O)n(C)c2ccccc12

Procedure:
Methyl 2-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.94 g, 1.4 mmol), methanol (0.33 ml, 8.1 mmol) and triphenyl phosphine (0.94 ml, 4.1 mmol) were placed in a 50 mL round bottomed flask with 25 mL of THF. The flask was placed in an ice bath. Diethyl azodicarboxylate (0.64 ml, 4.1 mmol) was added dropwise. A white solid was filtered and this solid was purified by silica flash chromatography (0-3% MeOH/DCM) to give the desired product.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[C:9]([CH2:10]O)=[CH:8][CH:7]=[CH:6][N:5]=1.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:1][CH2:3][C:4]1[C:9]([CH2:10][Cl:14])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: OCc1cccnc1CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: ClCc1cccnc1CCl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2-Hydroxymethyl-pyridin-3-yl)-methanol hydrogen chloride (26.79 g, 122 mmol) was added to thionyl chloride (33.8 mL) at 5° C. under an atmosphere of argon. The resulting mixture was allowed to warm to room temperature with stirred over 16 h. The resulting mixture was then evaporated in vacuo to yield 2,3-bis-chloromethyl-pyridine hydrogen chloride as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[Br:6][CH2:7][C:8](Br)=[O:9].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOCC>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:8](=[O:9])[CH2:7][Br:6]
Reactant: C#CCNC
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C#CCN(C)C(=O)CBr
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 13.8 g (0.2 mol) of N-methylpropargylamine in 20 ml methylene chloride was added dropwise to a stirred and cooled (below 15°C.) solution of 40.2 g (0.2 mol) bromoacetyl bromide and 16 g (0.2 mol) sodium bicarbonate in 250 ml methylene chloride. The reaction mixture was allowed to warm to about 25°C. and stirred for 2 hours. The reaction mixture was then filtered and evaporated under reduced pressure to give an oily residue. The residue was diluted with 150 ml ether to form a two-phase mixture consisting of an ether phase and a dark oil. The ether phase was separated, dried over magnesium sulfate, and evaporated to give 32.3 g of N-methyl-N-propargyl-α-bromoacetamide.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C(O[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:17]2[S:16][CH:15]=1)(=O)C>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH2:13][C:14]1[CH:19]([C:20]([OH:22])=[O:21])[N:18]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:17]2[S:16][CH:15]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: Oc1cccc(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccc(O)cc3O)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of 0.055 g of resorcinol in 0.3 ml of trifluoracetic acid is mixed with 0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and the solution is left to stand for 15 minutes at room temperature. It is diluted with an equal quantity of toluene and then evaporated to dryness under reduced pressure. 3-(2,4-Dihydroxybenzyl)-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is obtained by working up the residue in accordance with the process indicated in example 6; this acid shows the following Rf values in a thin layer chromatogram (silica gel): 0.66 (system n-butanol/acetic acid/water, 75:7.5:21), 0.70 (system n-butanol/acetic acid/water, 67:10:23) and 0.52 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](Cl)=[S:27])[CH3:24]>O>[N:7]1[C:8]2[C:3](=[C:2]([O:1][C:26](=[S:27])[N:25]([CH2:29][CH3:30])[CH2:23][CH3:24])[CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)C(=S)Cl
Reactant: Oc1cccc2nccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=S)Oc1cccc2nccnc12
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 5-hydroxyquinoxaline (2.13 g, 14.6 mmol), finely ground K2CO3 (4.0 g, 29 mmol), and DMF (50 mL) was stirred at 23° C. for 1 h. Solid diethylthiocarbamoyl chloride (2.43 g, 16.1 mmol) was then added. The resulting mixture was stirred for 2 h, then was diluted with water (150 mL) and extracted with Et2O (2×100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), then dried and concentrated to a viscous orange oil, which was used without purification (3.63 g, 95%). MS (ESI+): mass calcd. for C13H15N3OS, 261.1; m/z found, 262 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.85-8.65 (m, 2H), 7.96 (dd, J=8.5, 1.1, 1H), 7.71 (t, J=7.9, 1H), 7.46 (dd, J=7.6, 1.2, 1H), 3.87 (q, J=7.1, 2H), 3.78 (q, J=7.1, 2H), 1.38 (t, J=7.1, 3H), 1.28 (t, J=7.1, 3H). 13C NMR (125 MHz, CDCl3): 186.6, 149.4, 144.9, 144.5, 143.4, 137.0, 128.9, 127.0, 123.1, 48.2, 44.5, 13.1, 11.5.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:7](=[O:20])[N:6]=[CH:5]2.[CH:21]1([NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][C:25](=[O:42])[C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:7](=[O:20])[N:6]=[CH:5]4)[CH:27]=2)[CH2:22][CH2:23]1
Reactant: O=c1ncc2cc(Br)ccc2n1CCN1CCOCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(cnc(=O)n2CCN2CCOCC2)c1

Procedure:
The title compound was prepared as pale yellow solid, using 6-Bromo-1-(2-morpholinoethyl)quinazolin-2(1H)-one and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, by a method analogous to that described in Example 3 above. MS m/e 433 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Part A: To a stirred solution of ethyl 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (6.10 gram, 0.0139 mol) in THF (70 mL) is added LiOH (0.67 gram, 0.0278 mol) and water (70 mL). The resulting mixture is stirred for 16 hours at 50° C. to give a clear solution. After cooling to room temperature, HCl (1N solution, 28 mL) is added to give an oily precipitate which completely solidifies on continued stirring and addition of water (70 mL). The precipitate is collected by filtration, washed with water and dried in vacuo to give 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (4.92 gram, 86% yield). Melting point: 138–142° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:28].N1C=CC=CC=1.Cl>C(Cl)(Cl)(Cl)Cl>[CH2:30]([O:29][C:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:12][N:13]=2)=[CH:6][CH:7]=1)=[O:28])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCc1cnc(-c2ccc(OC(=O)OCCCCCCCCC)cc2)nc1
Reaction time: 8 h

Procedure:
2-(4-Hydroxyphenyl)-5-dodecylpyrimidine (G) (1.0 g) was dissolved in 50 ml of carbon tetrachloride, 0.8 ml of nonyl chlorocarboxylate and 5 ml of pyridine were added, and the mixture was stirred for a while and allowed to stand overnight. 1N Hydrochloric acid was added, and the carbon tetrachloride layer was taken and concentrated. The residue was purified by repeated recrystallization from methanol to obtain (H).
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>C1(C)C=CC=CC=1>[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8]
Reactant: CC1CCCN1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1
Product: CC1CCCN1CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of D series 2-(2-cyano-10-phenothiazinyl)-propyl methanesulphonate (6.8 g) in toluene (80 cc) and (2RS)-2-methylpyrrolidine (3.5 cc) is heated with stirring at 100° C. for 48 hours. After cooling to 25° C., the mixture is transferred into a separating funnel where it is washed with distilled water (2×200 cc) and brine (50 cc). The organic phase is dried over magnesium sulphate and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is purified by chromatography on a column (height: 35 cm; diameter: 3.2 cm) of silica (0.2-0.06 mm), eluting with a mixture of cyclohexane and ethyl acetate 70-30 (by volume) (1 liter), collecting fractions of 60 cc. Fractions 11 to 14 are pooled and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) to give 10-{1-[(2RS)-2-methyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazinecarbonitrile, D series (0.5 g), in the form of a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-:23][S:24]([O-:26])=[O:25].[Na+:27].[Na+].CCO>O>[Na+:27].[CH2:16]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24]([O-:26])(=[O:25])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCCc1ccccc1OCc1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCCc1ccccc1OCc1ccccc1

Procedure:
Following the procedure described for 11.1 using 10.3 (0.231 g, 0.64 mmol), Na2SO3 (0.11 g, 0.89 mmol) and EtOH (8 mL)/H2O (4 ml) mixture, the crude 11.3 was obtained and used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.C([N-]C(C)C)(C)C.[Li+].Br[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42].O>O1CCCC1>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[CH:40]([F:46])[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: CCOC(=O)C(F)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(F)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 200 mg, 0.49 mmol) in tetrahydrofuran (4 mL) is cooled in an ice bath. Lithium diisopropylamide (2 M in tetrahydrofuran, 270 μL, 0.54 mmol) is added, and the mixture is stirred for 15 min. Ethyl 2-bromo-2-fluoroacetate (135 mg, 0.73 mmol) is added, and the mixture is warmed at room temperature and stirred over night. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 70 mg; ESI mass spectrum [M+H]+=516; Retention time HPLC: 0.67 min (X012_S01).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.II.[CH3:12][C:13]([CH3:15])=O>>[Br:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([CH3:9])[CH:3]=1)[NH:6][CH2:15][CH:13]=[CH:12]2
Reactant: CC(C)=O
Reactant: Cc1cc(Br)ccc1N
Agent: II
Product: Cc1cc(Br)cc2c1NCC=C2

Procedure:
4-Bromo-2-methylaniline (5.58 g, 30 mmol) was treated with iodine (0.2 g, 0.9 mmol) and acetone (150 mL) in a sealed tube at 80° C. for 24 h to provide 6-bromo-1,2-dihydro-8-methylquinoline (Compound 85 of Scheme XXII) in 9% yield as a yellow oil (0.70 g). Most of the aniline (>80%) was recovered. A mixture of the 6-bromo-1,2-dihydro-8-methylquinoline (90 mg, 0.33 mmol), 3-nitrobenzeneboronic acid (167 mg, 1.0 mmol), Pd(PPh3)4 (24 mg, 0.02 mmol), K2CO3 (190 mg, 1.38 mmol) in toluene (7 mL) and water (1.5 mL) was heated to 70° C. for 16 h. Standard work-up followed by chromatography afforded 23 mg (23%) of Compound 292 as a yellow oil. Data for Compound 292: IR (neat) 3412, 2966, 1602, 1530, 1348; 1H NMR (400 MHz, CDCl3) 8.38 (t, J=2.0, 1H), 8.08 (dd, J=7.8 and 2.0, 1H), 7.85 (d, J=7.8, 1H), 7.52 (t, J=7.8, 1H), 7.24 (d, J=11.7, 1H), 7.21 (d, J=1.9, 1H), 5.39 (s, 1H), 3.72 (bs, 1H), 2.18 (s, 3H), 2.07 (s, 3H), 1.34 (s, 6H); 13C NMR (100 MHz, CDCl3) 148.9, 143.7, 142.0, 132.2, 129.6, 128.8, 128.7, 128.6, 126.5, 121.3, 121.0, 120.7, 120.6, 120.3, 52.3, 31.9, 19.2, 17.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10]C(=O)C.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([F:9])=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)Nc1cc(F)c(F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(F)c(F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
A solution of N-(2-chloro-4,5-difluorophenyl)acetamide (4.69 g, 22.8 mmol) in acetic acid (4.5 mL) and concentrated sulfuric acid (15 ml) was cooled to 0° C. To the solution was added a mixture of fuming nitric acid (2 mL) and acetic acid (0.5 mL). After stirring for 1.5 h at 0° C., the mixture was poured into ice. A precipitate formed, and it was collected by filtration. The filtrate was extracted with ether, and the organic phase was dried over magnesium sulfate, filtered, and concentrated to sticky yellow syrup. The solid and the syrup were combined, and to the resulting residue was added concentrated hydrochloric acid (30 mL). This mixture was heated to 120° C. for 1.25 h. It was then cooled to rt and subsequently poured onto ice. The aqueous solution was extracted with ethyl acetate. The organics were washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (80% hexanes: 20% ethyl acetate) to provide the desired 6-chloro-3,4-difluoro-2-nitroaniline (3.30 g, 15.8 mmol, 69% yield). 1H NMR (400 MHz, CDCl3): 7.43 (dd, 1H), 5.86 (br s, 2H); GCMS for C6H3ClF2N2O2: 208 (M+).
Reaction SMILES: [C:1](=[O:18])([O:15][CH2:16]Cl)[O:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4].[I-:19].[Na+]>C(#N)C>[C:1](=[O:18])([O:15][CH2:16][I:19])[O:2][C@H:3]([C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:4]
Reactant: C[C@H](OC(=O)OCCl)C(=O)OCc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: C[C@H](OC(=O)OCI)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
[(1S)-1-(benzyloxycarbonyl)ethyl] chloromethyl carbonate (2.7 g) was dissolved in acetonitrile (4 ml) and sodium iodide (6.0 g) was added. The mixture was stirred at 60° C. for 2 hours under an argon atmosphere. After the reaction mixture was concentrated under reduced pressure, diethyl ether (100 ml) and water (100 ml) were added to the residue. The diethyl ether layer was separated and washed with an aqueous 5% sodium thiosulfate solution (80 ml), water (80 ml), and a saturated sodium chloride aqueous solution (80 ml) successively. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain [(1S)-1-(benzyloxycarbonyl)ethyl] iodomethyl carbonate (3.3 g) as a colorless liquid.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8]#[N:9])[CH3:5]>CO.O>[CH2:4]([O:6][CH:7]([O:10][CH2:11][CH3:12])[C:8](=[NH:9])[O:2][CH3:1])[CH3:5]
Reactant: CCOC(C#N)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(OCC)C(=N)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
To a solution of sodium methoxide (13.38 g, 248 mmol) in MeOH (300 mL) was added dropwise 2,2-diethoxyacetonitrile (17.22 mL, 124 mmol). The resulting mixture was stirred at rt for 16 h. The reaction was then diluted with 300 mL of water and the product was extracted with 3×250 mL of Et2O. The combined Et2O layers were washed with 100 mL of brine, dried over sodium sulfate, and evaporated to give the desired product as a colorless liquid (15.3 g, 95 mmol, 77% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, br. s.), 4.77 (1H, s), 3.78 (3H, s), 3.55 (4H, qd, J=6.97, 4.28 Hz), 1.21 (7H, t, J=7.05 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:20][C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccncc2)CC1
Yield: 100.7 %

Procedure:
Amine preparation: a mixture of 1-BOC-piperazine (2 g), 4-pyridine carboxaldehyde (1.26 g), sodium triacetoxyborohydride (2.96 g) and acetic acid (0.6 mL) was stirred together in dry 1,2-dichloroethane (15 mL) at room temperature. After 4 h the reaction was quenched with saturated NaHCO3 solution and extracted with DCM, dried (Na2SO4), filtered and concentrated in vacuo to give 4-pyridin-4-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester (3 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, which was isolated as the hydrochloride salt.