Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([N:15]([CH3:16])[C:12]3[CH:13]=[CH:14][C:9]([CH2:8][N:6]4[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]4)=[CH:10][CH:11]=3)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)S(=O)(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.9 %

Procedure:
D3 (100 mg, 0.31 mmol) and triethylamine (65 ul, 0.47 mmol) were combined in dry DCM (3 mL) under argon. 4′-Fluoro-4-biphenylsulfonyl chloride (93 mg, 0.34 mmol) was added dropwise in a solution of dry DCM (3 mL). The reaction mixture was stirred at room temperature under argon for 19 h and diluted with DCM (20 mL) and washed with water then the organic layer was dried (Na2SO4) and concentrated in vacuo. The crude material was purified by chromatography eluting with 0-100% Et2O/petroleum ether to afford the title compound (53 mg), δH (CDCl3), 400 MHz: 1.23 (3H, d), 1.46 (9H, s), 2.01 (1H, m), 2.14, 1H, dd), 2.57 (1H, m), 2.74 (1H, m), 3.10 (1H, m), 3.21 (3H, s), 3.39-3.51 (2H, AB), 3.81 (1H, d), 4.19 (1H, br.s), 7.08 (2H, d), 7.17 (2H, t), 7.28 (2H, m), 7.57 (2H, dd), 7.61 (4H, s). MS (ES+): MH+ 554.3
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:36]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, (bromomethyl)benzene (0.67 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1(=O)[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH:15]=[CH:14][CH:13]=[C:12]3[C:11]1=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[C:10]1[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:21]=3[C:12]([C:11]1=[N:9]2)=[CH:13][CH:14]=[CH:15]4
Reactant: O=C1C(=O)c2cccc3cccc1c23
Reactant: Nc1ccc(Cl)cc1N
Product: Clc1ccc2nc3c(nc2c1)-c1cccc2cccc-3c12
Yield: 90 %

Procedure:
When 0.05 mole each of 4-chloro-o-phenylenediamine and acenaphthenequinone were reacted by the method of Example 7(A), 13 g. (90 percent yield) of 9-chloroacenaphtho-[1,2-b]quinoxaline, mp = 224°-225° C., were obtained
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12.[Br:24]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=3)[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2scc(-c3cccc(Br)c3)c2c1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(Br)c3)c2c1N
Reaction time: 3.5 h
Yield: 67.7 %

Procedure:
To a solution of ethyl 4-amino-3-(3-bromophenyl)-6-methylthieno[2,3-b]pyridine-5-carboxylate (Description 46) (6.309 g, 16.12 mmol) in DCM (100 mL) was added N-bromosuccinimide (3.44 g, 19.35 mmol) at RT. The mixture was stirred for 3.5 h. The solvent was removed in vacuo. The crude residue was then purified by chromatography on silica, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (5.13 g). LCMS (A) m/z: 471 [M+1]+, Rt 1.52 min (acidic).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:6]=1[NH2:12].[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16]>>[CH3:14][O:13][CH:3]([O:2][CH3:1])[CH2:4][C:5]1[C:6]2[NH:12][C:15](=[O:16])[NH:11][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(Cc1cccc(N)c1N)OC
Product: COC(Cc1cccc2[nH]c(=O)[nH]c12)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.6 %

Procedure:
3-(2,2-Dimethoxy-ethyl)-benzene-1,2-diamine (1.03 g, 5.26 mmol) was dissolved in dTHF and carbonyldiimidazole (935 mg, 5.77 mmol) added. The mixture was stirred at rt for 18 hours. The solvent was removed and the crude material chromatographed to afford 4-(2,2-dimethoxy-ethyl)-1,3-dihydro-benzoimidazol-2-one as a colorless solid (440 mg, 38%). 1H NMR (CDCl3) δ 3.03 (2H, d, J=5.2 Hz), 3.40 (6H, s), 4.58 (1H, t, J=5.2 Hz), 6.86-6.89 (m, 1H), 6.96-7.02 (m, 2H), 9.29 (br s, 1H), 10.28 (br s, 1H). MS: 221 (M−H)−.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1.[Cu][C:28]#[N:29].CN(C)C=O.Cl>O>[C:28]([C:2]1[C:7]2[O:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:24])[C:14]2=[O:25])=[C:4]([F:26])[CH:3]=1)#[N:29]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c3c2OC(C)(C)O3)c1=O
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(C#N)c3c2OC(C)(C)O3)c1=O
Temperature: 65 °C
Reaction time: 0.33 h

Procedure:
In a flask are placed 2.20 g (0.005 mole) of 3-(7-bromo-2,2-dimethyl-5-fluoro- 1,3-benzodioxol-4-yl)- 1 -methyl-6-trifluoromethyluracil, 0.62 g (0.0069 mole) of copper(I) cyanide and 60 mL of N,N-dimethylformamide. The resulting mixture is heated at reflux for 5 hours. This mixture is then cooled and poured into a solution of 2.5 g of hydrated ferric chloride, 0.62 mL of concentrated hydrochloric acid, and 3.8 mL of water. The resulting mixture is maintained at 60-70 ° C at which it is stirred for 20 minutes. After being cooled the mixture is extracted with methylene chloride, and the extract is washed with dilute hydrochloric acid. The extract is then dried over anhydrous magnesium sulfate, filtered, and the filtrate is evaporated under reduced pressure, leaving a residue. This residue is passed through a column of silica gel, eluting with ethyl acetate/heptane (1:1 ). The product-containing fractions are combined, and the solvent is evaporated under reduced pressure, leaving 3-(7-cyano-2,2-dimethyl-5-fluoro-1,3-benzodioxol-4-yl)-1-methyl-6-trifluoromethyluracil (Compound 15) as a residue.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:21][C:22]#[N:23].[Na+].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[NH2:23][C:22]([NH:15][N:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)=[O:21]
Reactant: N#C[O-]
Reactant: COC(=O)CN(N)c1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN(NC(N)=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A mixture of methyl [1-[4-phenoxyphenyl]hydrazino]acetate (Intermediate 76, 11 g, 0.004 mol), sodium cyanate (0.9 g, 0136 mol) and trifluoracetic acid (1 ml, 0.0124 mol) in dry toluene (15 ml) was stirred under nitrogen at room temperature for 1 hour. The mixture was poured into 8% sodium bicarbonate solution (75 ml) and extracted with ethyl acetate (2×75 ml). The organic extract was dried (MgSO4) and evaporated to give a pale yellow semi-solid. This was triturated with ether to give the title compound (Intermediate 77) as a white solid (0.6 g, 48%) m.p. 110°-113° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccccc2)c1O

Procedure:
20 mmol of methyl 3-amino-2-hydroxy-benzoate were stirred at room temperature in toluene with 20 mmol of benzoyl chloride for 4 hours with the addition of dimethylaniline, the mixture was concentrated and the residue was recrystallized from EtOH. M.p.: 105° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12].N#N.[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49](O)=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C)C=O>[C:36]([O:40][C:41]([NH:43][C@H:44]([C:49]([NH:8][C@@H:9]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:10]([OH:26])[C:11]([N:13]1[CH2:24][C@@H:23]([Cl:25])[CH2:22][C@H:14]1[C:15]([NH:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[O:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:42])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
4.4 ml (31.4 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 6.0 g (15.7 mmol) of (4S)-1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide [prepared as described in Preparation 21(b)] and 10.6 g (30.0 mmol) of the p-nitrophenyl ester of N2 -t-butoxycarbonyl-L-asparagine in 50 ml of dimethylformamide, and the resulting mixture was stirred for 3 days. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the residue was diluted with methylene chloride. The diluted solution was washed with a 5% w/v aqueous solution of citric acid, with a 1N aqueous solution of sodium hydroxide and with a saturated aqueous solution of sodium chloride, in that order, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was purified by column chromatography, using a 1:30 by volume mixture of methanol and methylene chloride as the eluent, to give 7.6 g of the title compound as a colorless powder, melting at 126°-132° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:12]1)=[O:5])C.[OH-].[K+]>C1COCC1.O>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:12]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCn1cc(C(=O)c2cccc3ccccc23)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCn1cc(C(=O)c2cccc3ccccc23)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2 (5.0 g, 12 mmol) in a mixture of THF/H2O (1:1) was added potassium hydroxide (1.7 g) and the mixture was stirred at 60° C. for 1 h. The THF was removed under vacuum, the aqueous solution acidified to pH 1 by the addition of hydrochloric acid solution (1N) and extracted by ethyl acetate (3×100 ml). The combined organic phases were washed by water (100 ml), brine solution (100 ml), dried over sodium sulphate, filtered and concentrated to dryness. The crude product obtained was dissolved in ethyl acetate (10 ml) and the Hapten-A precipitated by the addition of a mixture of ether/hexane as a white solid, filtered and dried under high vacuum to give Hapten-A (3.6 g, 78%).
Reaction SMILES: [NH2:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:1][CH2:2][N:3]1[CH2:7][CH:6]([CH2:8][CH2:9][CH3:10])[CH2:5][C:4]1=[O:11])([O-:21])=[O:20]
Reactant: CCCC1CC(=O)N(CN)C1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCC1CC(=O)N(CNc2ccccc2[N+](=O)[O-])C1

Procedure:
A mixture of 1-aminomethyl-4-propyl-pyrrolidin-2-one a27 (1 eq, 17.09 mmol, 2.67 g), 2-fluoro-nitrobenzene (1 eq, 17.09 mmol, 2.411 g, 1.802 ml) and triethylamine (1.1 eq, 18.8 mmol, 1.902 g, 2.62 ml) in dioxane (20 ml) was refluxed 48 h. After cooling, the crude mixture was filtrated and the dioxane was distilled under vacuum. The residue was purified by preparative chromatography on reverse phase to give (2-nitrophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a28 (2.747 g, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:40]1[CH:45]=[CH:44][C:43]([CH:46]=[CH:47][C:48](=[NH:50])[NH2:49])=[CH:42][CH:41]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:40]1[CH:45]=[CH:44][C:43]([CH:46]=[CH:47][C:48](=[NH:49])[NH2:50])=[CH:42][CH:41]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Oc1ccc(C=CC(=N)N)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)C=Cc1ccc(OC(=O)CCCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a solution of 4.5 g of 6-benzyloxycarbonylaminocaproic acid in 45 ml of dried pyridine, while being cooled in ice, was added 4.2 g of DCC. After 30 minutes of stirring, 4.4 g of 4-(β-amidinoethenyl)phenol methanesulfonate was added to the solution and stirred overnight at room temperature. The reaction mixture was freed from the precipitated DCU by filtration and the DCU was washed with pyridine. Ethyl ether was added to the combined filtrate to precipitate an oily substance. The oily substance was separated from the supernatant, washed a few times with ethyl ether, and dissolved in ethanol. Ethyl ether was added to the ethanol solution to precipitate a white solid substance which on recrystallization from an ethanol-ethyl ether mixture yielded 4.8 g of colorless granular crystals of 4-(β-amidinoethenyl)phenyl 6-benzyloxycarbonylaminocaproate methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>O>[Br:1][C:2]1[C:3](/[N:9]=[CH:12]/[N:13]([CH3:15])[CH3:14])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: COC(OC)N(C)C
Solvent: O
Product: CN(C)/C=N/c1ncc(Cl)cc1Br
Temperature: 100 °C
Reaction time: 1 h
Yield: 63483.8 %

Procedure:
A mixture of 3-bromo-5-chloropyridin-2-amine (10 g, 0.05 mol) and dimethoxy-N,N-dimethylmethanamine (7 g, 0.06 mmol) was stirred at 100° C. for 1 h. The mixture was poured into water and then extracted with Ethyl acetate (20 mL×4). The combined organic layer was concentrated under reduced pressure and the residue was purified with silica gel chromatography eluting with Ethyl acetate/PE (1:2) to afford 108a (10 g, 77%). LCMS: [M+H]+ 262.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>O1CCOCC1>[Cl:9][C:6]1[CH:7]=[CH:8][C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)=[C:3]([NH2:4])[CH:5]=1
Reactant: Nc1cc(Cl)ccc1Br
Reactant: CC1(C)OBOC1(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(Cl)cc2N)OC1(C)C
Temperature: 100 °C
Reaction time: 10.5 h
Yield: 67.2 %

Procedure:
To a solution of 2-bromo-5-chloroaniline (20.0 g, 96.9 mmol) in 1,4-dioxane (200 ml) were added triethylamine (54.0 ml, 487 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (3.96 g, 4.84 mmol), and under a nitrogen stream, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (42.3 ml, 290 mmol) was added dropwise. The mixture was stirred at 100° C. for 10.5 hr. The mixture was allowed to cool to room temperature and filtered through celite. To the filtrate was added dropwise methanol (25 ml) at 0° C. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=20:1) to give 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (16.5 g, yield. 65%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2.C(N(CC)CC)C>C(COC)OC>[N:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cccc2cccnc12
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C1CCCN1c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobutryl chloride (388.0 g) was added at 40° to a solution of technical grade 8-aminoquinoline (3396.5 g) and triethylamine (278.3 g) in dimethoxyethane (2 l). After stirring overnight at ambient temperature the solids were filtered off. The filtrate was concentrated prior to additon of 13% potassium tert-butoxide in tert-butanol (2486 g) at 25°-30°. After two hours the mixture was neutralized with dilute hydrochloric acid. The slurry obtained by partial removal of the solvent was extracted three times with methylene chloride. The combined extracts were washed with water, dried over magnesium sulphate, filtered and concentrated. Ether (1 l) was added while cooling to 0°. Filtration, followed by vacuum-drying afforded 1-(8-quinolyl)-2-pyrrolidinone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)([O-])=O.C(O)C.[H][H]>[Pd].CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: Cc1ccc2c(c1)C(=O)N(c1cc([N+](=O)[O-])ccc1C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)N(c1cc(N)ccc1C)C2=O

Procedure:
The mixture of 4.28 g of N-(4-nitro-o-tolyl)-4-methylphthalimide, 200 ml of 95% aqueous ethanol and 0.21 g of 5% palladium on charcoal is hydrogenated at 3.1 atm and 45° until the hydrogen uptake ceases. The resulting suspension is diluted with the minimum amount of dimethylformamide to solubilize the organic material, filtered and evaporated. The residue is taken up in chloroform, the mixture filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-4-methylphthalimide melting at 144°-147°.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=O)=[N:36]1.N1CCCCC1>CO>[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](/[CH:44]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)=[C:9]([O:25][CH2:26][CH2:27][O:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCOc3ccccc3)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0720 g, 0.154 mmol) in methanol (1 mL) was added with 1H-indazole-3-carboxaldehyde (0.0225 g, 0.154 mmol) and piperidine (0.00131 g, 0.0154 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-(2-phenoxyethoxy)-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0400 g, 43%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1.[C:18]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]2)=[CH:22][C:21]=1[F:34])#[N:19].[BH3-]C#N.[Na+].CC(O)=O>CO>[F:34][C:21]1[CH:22]=[C:23]([CH2:24][N:25]2[C:29]([CH2:30][NH:2][CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=3)=[CH:28][N:27]=[CH:26]2)[CH:32]=[CH:33][C:20]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Reactant: NCCc1ccccc1-c1cccc(O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CNCCc2ccccc2-c2cccc(O)c2)cc1F
Reaction time: 18 h

Procedure:
1-amino-2-(3′-hydroxybiphenyl-2-yl)ethane hydrochloride from Step C (0.47 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde from Example 3, Step G (112 mg, 0.49 mmol) were stirred in MeOH (1 mL) for 20 min, then NaCNBH3 (38 mg, 0.60 mmol) was added. The reaction mixture was adjusted to pH 5 with AcOH, as judged from wetted pH paper, and stirring was continued at ambient temperature for 18 hours. The reaction was quenched with 10% aq. citric acid and stirred for 20 min. Sat. aq. NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (3×20 mL).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1.[CH3:21][NH2:22]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:21])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2COCc3c(Cl)nc(Cl)nc32)cc1F
Reactant: CN
Product: CNc1nc(Cl)nc2c1COCC2c1ccc(F)c(F)c1

Procedure:
2,4-dichloro-8-(3,4-difluorophenyl)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation Y) was reacted as described in Preparation Xa with methanamine to give 2-chloro-8-(3,4-difluorophenyl)-N-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (Preparation Yc). LC-MS (M+H)+=312.3.