Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]2[O:22][CH:23]=[CH:24][N:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:26].[OH2:27].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].ClCCl.C(=O)([O-])O.[Na+]>CO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19]([CH3:20])(=[O:27])=[O:26])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]2[O:22][CH:23]=[CH:24][N:25]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: CSc1cnc2c(c1)cc(-c1ncco1)n2S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncco1)n2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A mixture of 1-benzenesulfonyl-2-(oxazol-2-yl)-5-methylthio-1H-pyrrolo[2,3-b]pyridine (28 mg), magnesium monoperoxyphtalate hexahydrate (116 mg, 80% purity), dichloromethane (1.2 ml) and methanol (0.5 ml) was stirred at 0° C. for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with dichloromethane, washed with a saturated aqueous NaCl solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane ethyl acetate=1:3) to obtain 14 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=O)[CH:18]=2)[NH:15][C:14](=[O:28])[CH:13]=[C:12]3[NH:29][CH:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[Cl:49][C:46]1[CH:45]=[CH:44][C:43]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([N:19]4[CH2:20][CH2:21][CH2:22][C:23]4=[O:25])[CH:18]=2)[NH:15][C:14](=[O:28])[CH:13]=[C:12]3[NH:29][CH:30]2[CH2:35][CH2:34][N:33]([S:36]([C:39]([F:41])([F:42])[F:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)=[CH:48][CH:47]=1
Reactant: CCOC(=O)CCCNc1cc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)cc(=O)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1CCCN1c1cc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc2c(NC3CCN(S(=O)(=O)C(F)(F)F)CC3)cc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of ethyl 4-((6-(bis(4-chlorophenyl)methyl)-2-oxo-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)-1,2-dihydroquinolin-8-yl)amino)butanoate (20 mg, 0.027 mmol) in THF (1 mL) was added 1N NaOH solution (0.12 mL) and mixture was stirred at room temperature for 3.5 hr. No more starting material was observed. The reaction was concentrated and neutralized to pH=5 with 1N HCl aqueous solution. The solid was extracted with EtOAc three times. The organics were concentrated and purified by chromatography (silica gel column, 100% EtOAc to yield 6-(bis(4-chlorophenyl)methyl)-8-(2-oxopyrrolidin-1-yl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-2(1H)-one.
Reaction SMILES: [CH2:1]([S:6]([OH:9])(=O)=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5].[Na].S(Cl)([Cl:13])=O>>[CH2:1]([S:6]([Cl:13])(=[O:9])=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCS(=O)(=O)O
Reactant: O=S(Cl)Cl
Agent: [Na]
Product: CCCCCS(=O)(=O)Cl
Temperature: 60 °C
Yield: 61 %

Procedure:
1-Pentanesulfonic acid, sodium salt (10 g, 57.5 mmol) was charged into a 250 ml round bottom flask (allow headroom). Thionyl chloride (20 mL) is added; gas evolves, and a while solid forms. The mixture is heated at 60° C. for 3 hours. The solvents are removed in vacuo; toluene is added and removed in vacuo to remove residue of SOCl2. The residue is partitioned between CH2Cl2 and ice water; the organic layer is dried over Na2SO4. The crude product is purified by distillation (bp 54–56° C. @ 0.5 mm Hg) to give a clear oil, 61% yield.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:24][C:25](=[O:43])[C@@H:26]([NH:31][C:32](=[O:42])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+:48].[K+].C(#N)C>CO.O>[K+:48].[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:24][C:25](=[O:43])[C@@H:26]([NH:31][C:32](=[O:42])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]([O-:23])=[O:22])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1OCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(OC(=O)N2CCC(C(N)=O)CC2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CO
Product: Cc1ccccc1OCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(OC(=O)N2CCC(C(N)=O)CC2)cc1)C(=O)[O-]
Temperature: 20 °C
Yield: 199.9 %

Procedure:
A suspension of Example 27 (10 g) in methanol (150 ml) was warmed to reflux to obtain a clear solution. To this was added a solution of potassium carbonate (1.16 g) in water (7.5 ml). After heating under reflux for two minutes the solvents were evaporated in vacuo to give a crisp foam. To this was added acetonitrile (100 ml) and the mixture was warmed to reflux, during which time the foam collapsed and started to crystallise. After ten minutes the mixture was allowed to cool to 20° C. then filtered under reduced pressure, washed with acetonitrile (25 ml) and ether (50 ml) to give the title compound as a white solid (10.65 g, 100%). The product is believed to be isolated in the form of its monohydrate. Solubility in water: >250 mg/ml.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([O:11]C)[CH:8]=[CH:9][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1
Reactant: COc1cccc(Oc2ccc(Cl)cc2Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Oc1cccc(Oc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
18.8 g of 3-(2,4-dichlorophenoxy)-anisole are added to a suspension of 37 g of anhydrous aluminium chloride in 80 ml of chlorobenzene and the mixture is stirred for 1 day at 60° C. The still hot solution is poured onto ice. The resulting mixture is extracted with toluene and the toluene solution is extracted with 2 N sodium hydroxide solution. The product is precipitated by acidifying the sodium hydroxide solution with dilute hydrochloric acid and extracted with toluene. The toluene solution is concentrated and the residue distilled in vacuo, affording 16 g of 3-(2,4-dichlorophenoxy)-phenol in the form of a colourless oil with a boiling point of 140°-145° C./0.05 torr. Using the corresponding chlorophenols as starting materials, it is possible to obtain the starting materials required for the production of the compounds of the formulae (302) to (304):
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH3:21][C:22]1([CH3:34])[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[C:31]([NH2:33])[CH:30]=[CH:29][CH:28]=2)[CH2:23]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:21][C:22]1([CH3:34])[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[C:31]([NH:33][C:2]3[C:3]4[N:4]([CH:18]=[CH:19][N:20]=4)[N:5]=[C:6]([C:8]4[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=4)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=3)[CH:30]=[CH:29][CH:28]=2)[CH2:23]1
Reactant: CC1(C)CCN(c2cccc(N)n2)C1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC(C)(C)C4)n3)c3nccn3n2)c1
Temperature: 100 °C
Yield: 82.9 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (0.10 g, 0.3 mmol), 6-(3,3-dimethylpyrrolidin-1-yl)pyridin-2-amine (60 mg, 0.3 mmol), Pd2(dba)3 (0.014 g, 0.03 mmol), BINAP (0.038 g, 0.06 mmol) and Cs2CO3 (0.3 g, 0.9 mmol) in dioxane (10 mL) was heated to 100° C. for 15 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, dichloromethane:MeOH=100:1) to afford methyl 3-(8-(6-(3,3-dimethylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (110 mg, 83%) as a brown solid. LC-MS: [M+1]+=443, tR=2.065 min.
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[OH:32].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[O:32][CH:2]([CH3:3])[C:1]([OH:4])=[O:5]
Reactant: O=C1CCO1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O
Yield: 44.3 %

Procedure:
β-Propiolactone (0.186 mL, 2.66 mmol) was added to a stirred, room temperature solution of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-phenol (1.5 g, 2.66 mmol), potassium tert-butoxide (0.314 g, 2.66 mmol) in THF (33 mL) under a dry nitrogen atmosphere. After 2 days the reaction mixture was added to water, acidified with 10% aqueous HCl and extracted with ethyl acetate. To the ethyl acetate phase was added acid washed (2% phosphoric acid in methanol) silica gel and the solvent was removed. The adsorbate was flash chromatographed (2% phosphoric acid in methanol treated silica gel ; eluent: gradient: 9:1 to 8:2 petroleum ether:ethyl acetate) to provide the title compound as an off-white solid (0.748 g, 44%): mp 218-220° C.: NMR (DMSO-d6);δ12.48 (broad s, 1H), 8.28 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (s, 2 H), 7.79 (ddd, J=7, 6, 1 Hz, 1 H), 7.64-7.57 (m, 2 H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.31 (ddd, =8, 7, 1 Hz, 1 H), 6.69 (d, J=8 Hz, 1 H), 4.44 (t, J=6 Hz, 2 H), 2.89 (t, J=6 Hz, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 632 (30%), 634 (70%) 636 (80%) 638 (40%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.68, H, 2.36, N, 0.01.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([CH3:10])=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=4)=[O:9])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Temperature: 79 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A dry 250 mL flask was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (0.989 g, 7.057 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (40 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.26 g, 4.994 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 4 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was suspended in boiling EtOAc. The suspension was allowed to cool to room temperature before filtering to afford the 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a tan solid (1.4 g, 3.74 mmol, 75%).
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:5][N:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.C1COCC1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]1[C:2]([C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[C:3]2[CH2:15][CH2:14][CH2:13][N:4]2[N:5]=1
Reactant: Brc1c(-c2ccccn2)nn2c1CCC2
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(-c2nn3c(c2-c2cccs2)CCC3)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 5.1 %

Procedure:
Add 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (Preparation 4, 250 mg, 0.95 mmol) and anhydrous THF (2.5 mL) to a round bottom flask under nitrogen atmosphere. Purge the reaction flask with nitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (87 mg, 0.095 mmol) and bis(1,2-bis(diphenylphosphino)ethane) palladium(0) (86 mg, 0.095 mmol) to the reaction flask, purge with nitrogen for 2 min, and then stir at room temperature for 20 min. Add thiophene-2-boronic acid (Maybridge; 120 mg, 0.95 mmol) in DMF (1 mL) to the reaction and stir for 10 min. Add 2M aqueous potassium carbonate (1.11 mL, 2.3 mmol) and heat the reaction mixture to 65° C. Add additional tris(dibenzylideneacetone) dipalladium(0) (87 mg, 0.095 mmol) to the reaction after 1 h, 3 h, and 5 h. Heat the reaction for a total of 20 h, cool to room temperature, and filter through Celite® with chloroform/methanol (250 mL, 1:1 ratio). Concentrate in vacuo and purify by flash column chromatography to provide the title compound (13 mg, 5%) as a pale, yellow solid. MS ESI+ m/e 268 (M+1). 1H NMR (CDCl3) δ 8.80-8.72 (m, 1H), 7.80-7.56 (m, 2H), 7.31-7.20 (m, 2H), 7.12-7.03 (m, 1H), 7.01-6.95 (m, 1H), 4.31-4.19 (m, 2H), 3.11-3.05 (m, 2H), 2.79-2.60 (m, 2H). HPLC: 98.0%, Rt=15.25 min. TLC (SiO2): Rf0.4 (5:95 methanol/dichloromethane).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[N:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])=[C:5]([O:19][Si](C(C)(C)C)(C)C)[CH:4]=1)#[N:2].C(N(C(C)C)CC)(C)C.Cl.[NH:37]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:38]1[C:39](OC)=[O:40].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CO>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[C:39](=[O:40])[CH:38]2[CH2:43][CH2:44][CH2:45][CH2:46][N:37]2[C:10]1=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[OH:19]
Reactant: COC(=O)C1CCCCN1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C#N)ccc1N=C=Nc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(N=C2N(c3ccccc3Br)C(=O)C3CCCCN23)c(O)c1
Yield: 75.2 %

Procedure:
The standard procedure was followed using N-(4-cyano-2-t-butyldimethylsilanoxyphenyl)-N′-(2-bromophenyl)carbodiimide (106 mg, 0.25 mmol), diisopropylethylamine (71 μL, 0.28 mmol), methyl pipecolinate hydro chloride (50 mg, 0.28 mmol) and TBAF (0.30 mL, 0.30 mmol) in THF (2.5 mL) and methanol (0.1 mL) to give 80 mg (75%) of 4-[[2-(2-bromophenyl)-1,5,6,7,8,8a-hexahydro-1-oxoimidazo[1,5-a]pyridin-3(2H)-ylidene]amino]-3-hydroxybenzonitrile as a tan powder. MS (EI) m/e 425 (100(M+)).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH3:27])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCOCC1>[CH2:1]([C:8]1[C:9]([CH3:27])=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ncc1Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(N2CCNCC2)ncc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(5-benzyl-4-methylpyrimidin-2-yl)piperazine-1-carboxylate (250 mg, 0.68 mmol) in dioxane (2 mL) was added 4 M HCl-dioxane (2 mL). The reaction mixture was stirred at RT for 2 h and then concentrated to afford crude 5-benzyl-4-methyl-2-(piperazin-1-yl)pyrimidine. MS (ES+) C16H20N4 requires: 268, found: 269 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8](Cl)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)nc(Cl)c1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
(2-Chloro-3-nitro-6-trifluoromethyl-pyridin-4-yl)-carbamic acid ethyl ester (300 mg, 0.96 mmol) was dissolved in 10 mL of tetrahydrofuran and benzylamine (0.103 mL, 0.96 mmol) was added followed by triethylamine (0.194 mL, 1.91 mmol) and the reaction mixture was stirred at 60° C. overnight. The solvent was removed and the solid was partitioned in ethyl acetate/water (50 mL/30 mL), the organic layer was dried over MgSO4, concentrated and purified by column chromatography on silica eluting with a gradient of 0% to 10% of methanol in ethyl acetate in to give 323 mg of the title compound as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].CC1C=CC(S(OC[C@H]2CCCN2C(OC(C)(C)C)=O)(=O)=O)=CC=1>>[C:1]([CH2:3][C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CC#N
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC#N

Procedure:
Prepared by proceeding in a similar manner to Intermediate 139, starting from tert-butyl (R)-2-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate 145) and used without further characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-methylacetophenone (R. Yveline, G. Gerard, and M. Geroges, Chem.Pharm.Bull., 1992, 40, 1170.). tlc: Rf=0.5 (25% ethyl acetate in hexanes)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.ClC1N=C(COC)NC=1C1C=C(C=CC=1C)C(O)=O.Cl.[NH:39]1[CH2:42][CH:41]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:40]1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[Cl:1][C:2]1[N:3]=[C:4]([CH2:17][OH:18])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:39]1[CH2:42][CH:41]([C:43]2[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=2)[CH2:40]1)=[O:12]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1Cl
Agent: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(CO)nc1Cl

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 27, except 3-(4-chloro-2-(hydroxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 28.1) was used in place of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used in place of 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2). m/z (ES+) 407 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([NH2:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([NH2:10])[CH2:8][NH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC(N)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: NCC(N)(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
α,α-Diphenyl-α-aminoacetonitrile (1.0 gm, 0.0048 mol) was dissolved in 6 ml of toluene and was cooled to -20° C. The solution was treated with 19.2 ml (0.0192 mol) of 1 M diisobutylaluminum hydride (DiBal-H) and stirred at -20° C. for 3 hours. The reaction mixture was quenched with 2.0 ml of methanol followed by 50 ml of water. The reaction mixture was acidified to pH 1.0 and the aqueous phase was extracted with ether several times. The remaining aqueous phase was basified to pH 13 with 2N sodium hydroxide solution and extracted with methylene chloride. The organic phase was dried and evaporated to afford 0.946 g (92%) of the desired material as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH2:10]([NH2:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(OCC)(=O)C>[OH:6][CH2:7][CH2:8][N:4]1[CH2:3][CH2:2][N:18]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]1=[O:9]
Reactant: CCCCCCCCN
Reactant: O=C1OCCN1CCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCN1CCN(CCO)C1=O
Reaction time: 8 h
Yield: 83 %

Procedure:
7.1 g of 3-(2-chloroethyl)oxazolidin-2-one was treated with 12.271 g of octyl amine. The reaction mixture was stirred overnight, diluted with ethyl acetate and washed with water and brine. The organic solution was dried and concentrated to give 9.55 g (83%) of product.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:30][C:26]=1[C:27](O)=[O:28].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:30][C:26]=1[C:27]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]=[C:7]2[O:6][C:5]1[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=1)=[O:28]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)nccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)nccc23)c1
Yield: 18.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 1-(4-fluoro-3-(trifluoromethyl)phenoxy)isoquinolin-5-amine (Intermediate-42, 80 mg, 0.24 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 134 mg, 0.49 mmol), oxalyl chloride (93 mg, 0.74 mmol), DMF (1 drop) and DIPEA (93 mg, 0.72 mmol) in CH2Cl2 (5 mL) to afford 26 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.30 (d, 1H), 8.21 (t, 1H), 8.08 (d, J=7.5 Hz, 1H), 7.98 (d, J=6.3 Hz, 1H), 7.82-7.55 (m, 7H), 7.37 (d, J=8.4 Hz, 1H), 4.32 (J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 574.22 (M+H)+.