Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:18](=[O:24])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH:11]([C:4]1[S:3][C:2]2[NH:1][C:18](=[O:24])[N:41]([CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:7](=[O:9])[C:6]=2[CH:5]=1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(C(C)C)sc1N
Reactant: NCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc2c(=O)n(CCc3ccccc3)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution (15 mL) of methyl 2-amino-5-isopropylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.98 g) and triethylamine (1.7 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (0.91 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), sodium methoxide (0.54 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.43 g, 54%).
Reaction SMILES: [Cl:1][CH:2]([NH:4][C:5](Cl)=[O:6])[CH3:3]>C(N=C=O)CCCCCN=C=O>[CH:2]([N:4]=[C:5]=[O:6])=[CH2:3].[Cl:1][CH:2]([N:4]=[C:5]=[O:6])[CH3:3]
Reactant: CC(Cl)NC(=O)Cl
Agent: O=C=NCCCCCCN=C=O
Product: C=CN=C=O
Product: CC(Cl)N=C=O
Yield: 53 %
Yield: 17.7 %

Procedure:
563 parts of 1-chloroethylcarbamyl chloride are dissolved in 2,800 parts by volume of hexamethylene diisocyanate. The solution, totalling 3,100 parts by volume, is introduced in 3 portions (500, 1,500 and 1,100 parts by volume) with different residence times (150, 310 and 225 minutes respectively) into a thin film evaporator operated under atmospheric pressure, with a counter-current of nitrogen. The jacket temperature is 73°-75° C. and the material passes over at 48°-54° C. The reaction product is collected in a receiver and two downstream cold traps, and the composition is determined by gas chromatography. 145.3 parts (53% of theory) of vinyl isocyanate, of boiling point 38.5° C./1,013 mbar, and 73.8 parts (17.7% of theory) of 1-chloroethyl isocyanate, of boiling point 92° C./1,013 mbar, are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:23])=[O:5]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(C(F)(F)F)c1Cl

Procedure:
To a suspension of 2-chloro-3-(trifluoromethyl)benzoic acid (15 g, 67 mmol) and catalytic DMF (0.06 mL, 0.67 mmol) in DCM (150 mL) was added oxalyl chloride (6.8 mL, 80 mmol) dropwise. The reaction was let stir (vigorous bubbling) for 4 h and concentrated to an oily solid which became solid after overnight drying on high vacuum.
Reaction SMILES: C([N:8]([CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]=1Br)[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])(OC(C)(C)C)=O.[C:41]([Li])([CH3:44])([CH3:43])[CH3:42].C[C:47]([OH:49])=[O:48]>C1COCC1>[F:26][C:25]([F:28])([F:27])[O:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([S:9]([NH:8][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]=3[C:47]([O:49][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:48])(=[O:10])=[O:11])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2ccccc2c1Br)S(=O)(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(CNS(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of Example 9D (1.50 g, 2.36 mmol) in THF (25 mL) under N2 at −78° C. was added tert-butyllithium (1.7 M in pentane, 3.0 mL, 5.10 mmol). The resulting reddish-purple solution was stirred for 30 minutes at the same temperature and then quenched with HOAc (0.56 mL, 9.77 mmol) and warmed to RT. The solvent was removed and the resulting oil was dissolved in ethyl acetate (100 mL), washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. Purification on silica gel with a gradient of 10% hexanes/CH2Cl2 to 3% ethyl acetate/CH2Cl2 provided 1.13 g (86%) of the desired compound as a white foam.
Reaction SMILES: [CH2:1]1[CH:6]([C:7]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][NH:3][CH2:2]1.[OH-].[K+].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]Cl)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[OH:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]1[CH2:5][CH2:4][N:3]([CH2:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:2][CH2:1]1
Reactant: COc1ccc(CCCl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1

Procedure:
A mixture of 4 g of α,α-diphenyl-4-piperidinomethanol, 0.94 g of powdered potassium hydroxide and 200 mg of KI are dispersed in 50 ml of toluene in a 250 ml round-bottomed flask. Addition of 2.3 ml of 4-methoxyphenylethyl chloride is followed by heating under reflux for 3 days.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][O:14][C:15]1[C:16]([CH3:28])=[C:17]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21].[OH-].[Na+]>C(O)C>[OH:4][C:3]1[CH2:2][CH:23]([C:17]2[C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]([O:14][CH3:13])[C:16]=2[CH3:28])[CH2:24][C:25](=[O:27])[CH:26]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1c(C)cc(C)c(C=CC(C)=O)c1C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cc(C)c(C2CC(=O)C=C(O)C2)c1C
Yield: 63 %

Procedure:
Diethyl malonate (21.0 g) was added to a solution of sodium metal (3.02 g) in anhydrous absolute ethanol (55 ml) and the mixture was heated to reflux temperature. 1-(3-Methoxy-2,4,6-trimethylphenyl)but-1-en-3-one (27.3 g) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (16.0 g in 100 ml of water) was added and the mixture was heated under reflux for a further 41/2 hours. The aqueous mixture was cooled and washed with dichloromethane and the aqueous phase was warmed, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to give 3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (20.5 g) as a colourless crystalline solid, mp 165°-166° C.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[Cl:14].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1>CS(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[Cl:14])[O:15][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][N:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c(Cl)c2)nc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 44.9 g of t-BuOK in 250 ml of DMSO was added 65.2 g of 3,4-dichlorophenol in 50 ml of DMSO causing a temperature rise to between 65°-70° C. To this warm solution was added 2-chloro-5-nitropyridine (63.4 g) which raised the temperature to 90° C. The mixture was stirred without heating until the temperature dropped to 40° C. (~1 hr). The reaction mixture was poured into 1 kilogram (kg) of ice-water and the solid collected by filtration. The solid was dissolved in CH2Cl2, dried over Na2CO3, treated with charcoal, redried over MgSO4 and then filtered. The CH2Cl2 solution was concentrated to 250 ml, then diluted to 700 ml with hexane and allowed to stand overnight. From this solution, a crystalline material was collected by filtration and 94.8 g of 2-(3,4-dichlorophenoxy)-5-nitropyridine obtained, m.p. 101°-102.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Br:12])[CH:3]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.OOS([O-])=O.[K+]>CN(C=O)C.O>[Br:12][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]2[N:10]([CH3:11])[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:1][C:2]=2[CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: CNc1cc(C#N)c(Br)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(-c2cccnc2)nc2cc(Br)c(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To solution of 4-amino-2-bromo-5-(methylamino)benzonitrile (0.2 g, 0.0008 mol) and nicotinaldehyde (0.094 g, 0.0008 mol) in DMF (5 ml) and H2O (2 ml) was added OXONE® monopersulphate (0.43 g, 0.0007 mol). Reaction mass was stirred at room temperature for 3 h. The reaction mixture was quenched with 10% K2CO3 solution to PH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 5-bromo-1-methyl-2-(pyridin-3-yl)-1H-benzimidazole-6-carbonitrile. (3971H NMR (400 MHz, DMSO-d6), δ: 9.08 (s, 1H), 8.80-8.79 (d, J=4 Hz, 1H), 8.53 (s, 1H), 8.34-8.32 (d, J=7.2 Hz, 1H), 8.23 (s, 1H), 7.67-7.63 (m, 1H), 3.96 (s, 3H). MS (M+1): 313.12, Purity 93.84%.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:8]3[NH:12][C:11]([C:13]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[C:14]4[CH:42]=[CH:41][C:16](=[C:17]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:18]5[CH:34]=[CH:33][C:20](=[C:21]([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[C:22]6[CH:23]=[CH:24][C:25]=2[N:26]=6)[N:19]=5)[NH:15]4)=[CH:10][CH:9]=3)=[CH:5][CH:6]=1.[Pd:49](Cl)Cl.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:43]1([C:13]2[C:11]3[NH:12][C:8](=[CH:9][CH:10]=3)[C:7]([C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[C:25]3[N:26]=[C:22]([CH:23]=[CH:24]3)[C:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:20]3[NH:19][C:18]([CH:34]=[CH:33]3)=[C:17]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:16]3=[N:15][C:14]=2[CH:42]=[CH:41]3)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[Pd:49]
Reactant: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Reactant: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Product: [Pd]

Procedure:
Palladium tetraphenylporphyrin is prepared according to the method of operation described by D. W. Thomas and A. E. Martell, J. Amer. Chem. Soc., Vol. 81, p. 5111 (1959). 10 grams of purified tetraphenylporphyrin and 7.7 grams of palladium chloride are placed in 385 ml of acetic acid. The mixture is refluxed for 10 minutes, then 23 grams of sodium acetate are added and the mixture is refluxed for an hour and then a further 23 grams of sodium acetate are added. After 2 additional hours under reflux, the mixture is allowed to cool and poured into 800 ml of water. The precipitate is obtained by filtration, washed with water and, after drying, 12.3 grams of the Pd complex is obtained.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[H-].[Na+].C1(P(C2C=CC=CC=2)(O[NH2:27])=O)C=CC=CC=1>CN(C=O)C>[NH2:27][N:7]1[C:6](=[O:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3][CH:2]1[CH3:1]
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1N
Temperature: 50 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-methyl-5-oxo-1-piperazinecarboxylate (1.1 g) was dissolved in DMF (20 ml) and treated with sodium hydride (0.25 g, in oil) with cooling on ice. After stirring at 50° C. for 1 hour, O-diphenylphosphinyl hydroxylamine (1.3 g) was added and the mixture was stirred at 50° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was combined with aqueous sodium bicarbonate and extracted with dichloromethane. The extract was dried and concentrated to obtain tert-butyl 4-amino-3-methyl-5-oxo-1-piperazinecarboxylate as a yellow oil.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:9](O)C.[Cl:12][C:13]1[CH:32]=[CH:31][C:16]([CH2:17][NH:18][C:19]([C:21]2[C:22]([OH:30])=[C:23]3[CH:29]=[CH:28][S:27][C:24]3=[N:25][CH:26]=2)=[O:20])=[CH:15][CH:14]=1>C(O)(=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]([C:21]2[C:22]([OH:30])=[C:23]3[CH:29]=[C:28]([CH2:9][N:3]4[CH2:8][CH2:7][O:6][CH2:5][CH2:4]4)[S:27][C:24]3=[N:25][CH:26]=2)=[O:20])=[CH:31][CH:32]=1
Reactant: C1COCCN1
Reactant: CCO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sccc2c1O
Agent: C=O
Solvent: CC(=O)O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Yield: 55 %

Procedure:
Formaldehyde (2.6 mL) is added to morpholine (2.7 mL) at 0° C. Ethanol (10 mL) is then added followed by addition of N-(4-chlorobenzyl)-4-hydroxythieno[2,3-b]pyridine-5-carboxamide (1.00 g) from Example No. 1. Acetic acid (2 mL) is added, and the reaction mixture is allowed to warm to rt and then refluxed for 18 h. Additional morpholine (2.7 mL) and formaldehyde (2.6 mL) are added and the reaction is refluxed for an additional 24 h. The reaction mixture is allowed to cool to room temperature and is then concentrated in vacuo. The residue is treated with 25% NaOH (20 mL). The aqueous layer is extracted with ethyl acetate (50 mL) then CHCl3 (60 mL). Methanol (30 mL) is added to the aqueous layer and it is extracted with CHCl3 (2×60 mL). This procedure is repeated 3 times. The combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting brown solid is purified by column chromatography (CH2Cl2/methanol, 98/2; 96/4) to yield a tan solid which is recrystallized from ethyl acetate/Et2O to yield 0.718 g (55%) of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(F)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(F)c1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of 3-fluorobenzaldehyde (10 g), malonic acid (15.6 g) and piperidine (0.7 ml) in pyridine (35 ml) was heated at reflux for 3.5 hours. After cooling to room temperature, the reaction mixture was added to a mixture of ice water (210 ml) and conc. hydrochloric acid (56 ml). The precipitate was isolated by filtration and recrystallized from methanol/water to give 3-fluorocinnamic acid (11.3 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24].I[C:26]1[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:26]3[N:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:22][CH2:23][OH:24]
Reactant: Cc1ccc(I)nn1
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)nn1

Procedure:
To a stirring solution of 2-{5-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-oxazol-4-yl}-ethanol (0.314 g, 0.952 mmol) (See Intermediate 3), 3-Iodo-6-methyl-pyridazine (0.178 g, 0.810 mmol) [CAS# 1618-47-9] and [1,1 bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (1:1) (0.02 g, 0.024 mmol) in 10 mL dioxane is added aqueous sodium carbonate (2M, 1.22 mL) and the reaction is carried out substantially in accordance with the procedure of Example 9 to provide after purification by radial chromatography pure titled compound (0.208 g, 87%). MS (m/e): 296.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[N:4][CH:5]=[N:6][C:7]=1[NH:8][CH3:9].[CH3:26][N:27]1[CH:31]=[C:30]([CH:32]=O)[CH:29]=[N:28]1.Cl>C(O)C>[CH3:9][N:8]1[C:32]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:1][C:2]2[C:7]1=[N:6][CH:5]=[N:4][C:3]=2[N:10]1[CH2:11][CH2:12][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:14][CH2:15]1
Reactant: CNc1ncnc(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)c1N
Reactant: Cn1cc(C=O)cn1
Agent: Cl
Solvent: CCO
Product: Cn1cc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of 1-(1-(5-amino-6-(methylamino)pyrimidin-4-yl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (70 mg, 0.2 mmol) in anhydrous ethanol (8 mL) were added 1-methyl-1H-pyrazole-4-carbaldehyde (34 mg, 0.3 mmol) and catalytic amount of hydrochloric acid (0.05 mL, 4M HCl in Dioxane, Aldrich). The reaction mixture was heated to 80° C. for 18 hours. The resulting precipitate was collected by vacuum filtration, washed with ethanol (2 mL) and dried under reduced pressure, to give 62.6 mg (70% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), 7.13 (dd, 1H), 6.93 (m, 3H), 4.53 (m, 1H), 3.92 (s, 3H), 3.81 (d, 3H), 3.33 (m, 2H), 3.24 (m, 2H), 2.33 (m, 2H), 1.82 (d, 2H); MS (EI) for C22H23N9O: 430.4 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=2[S:5](=[O:14])(=[O:13])[C:4]1([CH3:16])[CH3:15].Br[C:18]1C=CC2C(C)(O)C(C)(C)S(=O)(=O)C=2C=1>>[CH3:1][O:2][C:3]1([CH3:18])[C:7]2[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=2[S:5](=[O:14])(=[O:13])[C:4]1([CH3:16])[CH3:15]
Reactant: COC1c2ccc(Br)cc2S(=O)(=O)C1(C)C
Reactant: CC1(O)c2ccc(Br)cc2S(=O)(=O)C1(C)C
Product: COC1(C)c2ccc(Br)cc2S(=O)(=O)C1(C)C

Procedure:
Following the general method as outlined in Intermediate 248, starting from 6-bromo-2,2,3-trimethyl-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide (Intermediate 246), the title compound was obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](O)=[O:22])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH:26]([N:29](CC)[CH:30](C)C)(C)C.CNC.CCO.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[CH3:26][N:29]([CH3:30])[C:21](=[O:22])[CH2:20][O:19][CH:16]1[C:12]2[CH:13]=[N:14][CH:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([F:2])([F:24])[F:25])=[CH:5][CH:6]=3)[C:11]=2[CH2:18][CH2:17]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CNC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (70 mg, 0.19 mmol) in THF (0.6 mL) was added N,N-diisopropylethylamine (131 μL, 0.75 mmol), N,N-dimethylamine 33% solution in EtOH (67 μL, 0.38 mmol) and 1-propanephosphonic acid cyclic anhydride (284 μL, 0.47 mmol). The reaction was stirred at room temperature for 16 h. The mixture was evaporated and purified by flash chromatography (20 g SiO2, Telos-cartridge, 4% 2-propanol in CH2Cl2) to give the title compound (49 mg, 72%) as yellow oil. MS: 365.6 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][C:23]=1[C:24](O)=[O:25].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:27][C:23]=1[C:24]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[O:8][CH:5]1[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]1)=[O:25]
Reactant: CC1(C)CCC(Oc2ncnc3c(N)cccc23)CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)CCC(Oc2ncnc3c(NC(=O)c4cc(CNC(=O)C(C)(C)C)ccc4Cl)cccc23)CC1
Yield: 51.7 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-((4,4-dimethylcyclohexyl)oxy)quinazolin-8-amine (Intermediate-10, 50 mg, 0.185 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 99 mg, 0.369 mmol), oxalyl chloride (70 mg, 0.55 mmol), DMF (1 drop) and DIPEA (72 mg, 0.56 mmol) in CH2Cl2 (3 mL) to afford 50 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.24 (s, 1H), 8.80 (s, 2H), 8.18 (m, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.73-7.71 (m, 1H), 7.59-7.54 (m, 2H), 7.39 (d, J=7.8 Hz, 1H), 5.38 (m, 1H), 4.30 (d, J=6.0 Hz, 2H), 1.95 (m, 2H), 1.81 (m, 2H), 1.51 (m, 2H), 1.34 (m, 2H), 1.12 (s, 9H), 1.00 (s, 3H), 0.97 (s, 3H); MS (m/z): 523.07 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:29][C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:29][C:30]([N:1]1[C:10]2[C:5](=[CH:6][C:7]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11][C:8]=3[CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:32]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)NCCC3
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C(=O)Cl)CCC3
Reaction time: 3 h
Yield: 193.6 %

Procedure:
To a solution of 3.83 g of t-butyl 1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate in 40 ml of dichloromethane were added 1.3 ml of pyridine and 1.29 g of triphosgene under ice-cooling, followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and an aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. To the residue was added hexane, followed by stirring, and the solid was collected by filtration and dried to obtain 3.07 g of t-butyl 1-(chlorocarbonyl)-1,2,3,4,6,7,9,10-octahydro-8H-azepino[4,5-g]quinoline-8-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1B(O)O.Br[C:16]1[N:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>[Pd].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:16]1[N:17]=[CH:18][C:19]([NH:22][C:23](=[O:32])[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])=[N:20][CH:21]=1
Reactant: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Reactant: OB(O)c1cc(C(F)(F)F)ccc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1c(F)cccc1F
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-benzeneboronic acid (a, 5 mmol), N-(5-bromo-pyrazin-2-yl)-2,6-difluoro-benzamide (b, 5 mmol), palladium catalyst (0.30 mmol), potassium carbonate (1 g) in dry 1,4-dioxane (20 mL) was heated at 100° C. for 24 h. The mixture was taken up with ethyl acetate (EtOAc) (100 mL), washed with water (2×100 mL) and dried over Na2SO4. The oil obtained on concentration was purified by flash chromatography followed by recrystallization to give Compound 1 as a yellowish solid (0.19 g).