Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].Cl.Cl.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH:19]1[C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([N:21]1[CH2:22][CH2:23][NH:18][CH:19]([C:24]([O:26][CH3:27])=[O:25])[CH2:20]1)=[O:7]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)C1CNCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution of 3,4,5-trimethoxybenzoyl chloride (10.9 g) in dichloromethane (100 ml) is added dropwise taking one hour, under ice-cooling while stirring, to a mixture of methyl piperazine-2-carboxylate dihydrochloride (10.24 g), triethylamine (18.7 g) and dichloromethane (200 ml). The reaction mixture is poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. Crystals obtained from the residue are recrystallized from ethyl acetate and hexane to afford methyl 4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (9.6 g) as colorless needles, m.p. 113-114° C.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][OH:15])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:15][CH2:14][CH2:13][CH:10]1[CH2:11][CH2:12][C:7]2([O:6][CH2:5][CH2:4][O:3]2)[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCC1CCC2(CC1)OCCO2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a precooled (0° C.) suspension of NaH (60% in mineral, 0.44 g, 11 mmol) in THF (20 mL) was added 2-(1,4-dioxaspiro[4.5]decan-8-yl)ethanol (1.86 g, 10 mmol) in THF (10 mL). The resulting solution was stirred at 0° C. for 10 min, and allowed to warm to RT, and stirred for 1 h. To the above mixture was added benzyl bromide (1.78 g, 15 mmol) and the resulting mixture was stirred at rt overnight. The reaction was quenched by addition of saturated aqueous NH4Cl solution, extracted with EtOAc, washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes to 30%) gave the product (2.3 g, 83%). LC/MC: 277.1 (MH)+.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=O.N[C:16]1[C:20]([C:21]#[N:22])=C[NH:18][N:17]=1>C(O)(=O)C>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:18]3[N:17]=[CH:16][C:20]([C:21]#[N:22])=[C:14]3[N:2]=[CH:3][CH:4]=2)=[N:8][CH:9]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: Cc1ccc(C(=O)C=CN(C)C)nc1
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccnc3c(C#N)cnn23)nc1

Procedure:
A miture of 0.01 mole of 3-dimethylamino-1-(5-methyl-2-pyridyl)-2-propen-1-one and 0.01 mole of 3-aminopyrazole-4-carbonitrile in glacial acetic acid is refluxed for 8 hours and worked up as for Example 53 to give the product of the example.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>N.CO.O.C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][CH2:21][CH2:22][NH:23][C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)C(=O)NCCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: N
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)NCCC#Cc1c(Cl)ccc2c1CCNCC2
Yield: 94.4 %

Procedure:
Use a method similar to the General Procedure 1-1, using 7N ammonia in methanol/water/THF (10:1:1 ratio) as solvent, to deprotect 7-chloro-6-[4-(2,2-dimethyl-propionylamino)-but-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (62 mg, 0.14 mmol) and afford the title compound as an oil (44 mg, 91%). MS (ES+) m/z: 333.1 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13](Cl)[C:7]2=[CH:6][C:5]=1[NH:17]C(C)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[F:29])[NH2:25].CC(O)C.Cl>CS(O)(=O)=O.O>[NH2:17][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:4]=1[O:3][CH2:2][CH3:1])[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13]2[NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:29])=[C:22]([Cl:21])[CH:23]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Temperature: 84 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
A stirred mixture of N-(4-chloro-3-cyano-7-ethoxy-6N-acetylquinoline (274.5 g, 0.947 mol), 3-chloro-4-fluoroaniline (180 g, 1.24 mol), methanesulfonic acid, (5.5 g, 0.057 mol), and 2-propanol (6.7 L) was warmed to reflux (84° C.) for 6.5 hours. After stirring overnight at room temperature, the mixture was warmed to 80° C. Water (3.2 L) containing concentrated hydrochloric acid (655 mL of 38% aqueous HCl) was added. The reaction was kept at reflux for 5 hours. The reaction mixture was cooled to 0° C.-10° C. for 1 hour. The yellow solid product is collected by vacuum filtration and washed with 20% 2-propanol/water (700 mL) and water (2×700 mL). Drying the product in vacuo at 60° C. gave 344.8 g (91%, 99% by HPLC) of 6-Amino-4-(3-chloro-4-fluoro-phenylamino)-7-ethoxy-quinoline-3-carbonitrile as a hydrochloride salt. 1H NMR (DMSO-d6+D2O) δ1.42 (t, 3H), 4.25 (q, 2H), 7.05 (m, 1H), 7.1 (s, 1H), 7.35-7.50 (m, 3H), 7.65 (dd, 1H), 8.65 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9](Cl)(=[O:12])[CH2:10][CH3:11].Cl>>[C:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:12])[CH2:10][CH3:11]
Reactant: CCC(=O)Cl
Reactant: Oc1ccccc1Cl
Agent: Cl
Product: CCC(=O)Oc1ccccc1Cl
Temperature: 100 °C
Yield: 85.4 %

Procedure:
o-Chlorophenol (64 g, 0.5 mole) and propionyl chloride (50 g, 0.55 mole) were mixed at room temperature and then heated at 100° C. (steam bath) for 2-3 hrs. Hydrogen chloride gas was evolved. After 2-3 hrs the reaction mixture was distilled in vacuo and gave 78.8 g (86%) of o-chlorophenyl propionate, bp 11 mm =111° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:13]2[CH2:18]CO[CH2:15][CH2:14]2)=[C:7]([NH:9][C:10]([NH2:12])=S)[CH:8]=1)#[N:2].[C:19](=[O:22])([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH3:27].O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>C(O)C>[CH3:25][N:26]([CH3:27])[C:10]([NH2:12])=[N:9][C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[N:13]1[CH2:18][CH2:19][O:22][CH2:15][CH2:14]1
Reactant: CNC
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(N2CCOCC2)c(NC(N)=S)c1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Pb+2]
Solvent: O
Solvent: CCO
Product: CN(C)C(N)=Nc1cc(C#N)ccc1N1CCOCC1

Procedure:
A mixture of 1-(5-cyano-2-morpholinophenyl)thiourea (5.2 g), potassium carbonate (8.3 g), a 33% ethanolic solution of dimethylamine (15 ml), lead acetate trihydrate and ethanol (25 ml) was heated under reflux for 3 hours to yield 1,1-dimethyl-2-(5-cyano-2-morpholinophenyl)guanidine (m.p. 125°-127° C.) which was converted into its monofumarate salt [m.p. 223°-225° C. (dec)] which was recrystallised from methanol.
Reaction SMILES: [NH2:1][C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N([C:54]([O:56][CH2:57][CH:58]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:64]2[C:59]1=[CH:60][CH:61]=[CH:62][CH:63]=2)=[O:55])[C@H](C(O)=O)CSC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.S(=O)(=O)(O)O>CO>[NH:1]([C:54]([O:56][CH2:57][CH:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:65]2[C:70]1=[CH:69][CH:68]=[CH:67][CH:66]=2)=[O:55])[C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
and H2N-Cys(Trt)-OMe 26. 7.2 g (12.3 mmol) of Fmoc-Cys(Trt)-OH was dissolved in 70 ml of MeOH and added 1.5 ml of conc. sulfuric acid. The reaction mixture was refluxed for 4 hr, the solvent was removed. The mixture was then mixed with ethyl acetate, and washed with water, saturated NaHCO3, and brine. Removing the solvent under vacuum gave 25 as a white foamy solid. The crude product was dissolved in 20 ml of 20% piperidine solution in DMF. After 2 hr, the solvent was removed. Silicagel chromatography (CH2Cl2: MeOH=10:1) gave 4.0 g (86% two step yield) of 26 as a white solid.
Reaction SMILES: [CH:1]1([C:7]2([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH2:9][CH2:10][CH2:11]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: C=CC(=O)Cl
Reactant: OC1(C2CCCCC2)CCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C2CCCCC2)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
In 1 liter of methylene chloride was dissolved 92.4 g of 1-cyclohexylcyclopentanol. To the solution below −20° C., 74.3 g of acrylic chloride was added dropwise over 10 minutes. To the reaction mixture, 1.0 g of 4-(N,N-dimethylamino)pyridine was added and then, 125.0 g of triethylamine was added dropwise over one hour and below −20° C. This reaction mixture was agitated for 15 hours at room temperature and subjected to conventional post-treatment, obtaining an oily substance. Vacuum distillation yielded 110.5 g of 1-cyclohexylcyclopentyl acrylate (designated Monomer 1). The yield was 90.5%. Boiling point: 83-85° C./53.3 Pa
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=C(\C)/CCC(OC)=O)=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[O:38]=[O+][O-]>C(Cl)Cl.CO>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]=[O:38])=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (10.6 g) in methylene chloride (150 ml), methanol (150 ml), and pyridine (5 ml) was treated with an excess of ozone at -70° C. The reaction was quenched with dimethylsulfide (20 ml) and stirred for 5 hours at 25° C. The reaction mixture was poured into 1N aqueous sodium hydrogen sulfate. Extraction with 1:1 ethyl acetate:hexane gave an oil which on purification by silica gel chromatography gave 2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 90.9°-91.6° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([CH3:10])[C:6](=[O:9])[NH:7][N:8]=1)[CH3:2].[Cl:11][S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13]>C(Cl)Cl>[Cl:11][S:12]([NH:15][C:16]([N:7]1[C:6](=[O:9])[N:5]([CH3:10])[C:4]([O:3][CH2:1][CH3:2])=[N:8]1)=[O:17])(=[O:14])=[O:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOc1n[nH]c(=O)n1C
Solvent: ClCCl
Product: CCOc1nn(C(=O)NS(=O)(=O)Cl)c(=O)n1C
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
28.8 g (0.20 mol) of 5-ethoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are introduced into 250 ml of methylene chloride, and the mixture is cooled to -10° C. 28.3 g (0.20 mol) of chlorosulphonyl isocyanate are added to this mixture, and the reaction mixture is stirred for 30 minutes without cooling. The solvent is then carefully removed by distillation under water pump vacuum. 53 g (93% of theory) of 2-chlorosulphonylaminocarbonyl-5-ethoxy-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one are obtained as a crystalline residue of melting point 106° C.
Reaction SMILES: P([CH2:5][C:6]([O:8][CH3:9])=[O:7])(O)(O)=O.[H-].[Na+].[H][H].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][CH:23]=[C:24]([CH:25]=O)[C:18]=2[CH:17]=1.P(=O)([O-])[O-]>O1CCCC1.ClCCl>[CH3:9][O:8][C:6](=[O:7])[CH:5]=[CH:25][C:24]1[C:18]2[C:19](=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[NH:22][CH:23]=1
Reactant: COc1ccc2[nH]cc(C=O)c2c1
Reactant: COC(=O)CP(=O)(O)O
Reactant: [H][H]
Agent: O=[PH]([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C=Cc1c[nH]c2ccc(OC)cc12
Temperature: 55 °C
Yield: 78 %

Procedure:
To a cold solution (ice bath) of methyl phosphonoacetate (13.74 g, 0.065 mol) in tetrahydrofuran (120 mL) under nitrogen, was added sodium hydride (2.6 g, 0.065 mol, 60%) in one portion, and stirred until hydrogen evolution ceased. A solution of commercially available 5-Methoxyindole-3-carboxyaldehyde 2 (5.2 g, 0.029 mol) in tetrahydrofaran (80 mL) was added, over a period of 60 minutes, to the phosphonate solution. The reaction mixture was heated to 55° C. for 24 h after which the mixture was diluted with dichloromethane (DCM, 500 mL) and washed with water (200 mL; 3×). The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give yellow-tinted oil and purified by filtering through a silica plug. The filtrate was evaporated to afford 3 as an off white solid (6.2 g; 78% yield; M+1=232.0).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:20])[CH:14]=2)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26]([C:28]1([CH2:41][CH:42]=O)[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)=O)C.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:37]([O:36][C:34]([N:31]1[CH2:32][CH2:33][C:28]2([C:26](=[O:25])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([CH:10]4[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21])[CH2:8][CH2:9]4)=[CH:14][C:15]=3[F:20])[CH2:42][CH2:41]2)[CH2:29][CH2:30]1)=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2ccc(N)c(F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(O[Si](C)(C)C(C)(C)C)CC3)cc1F)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohexyl]-2-fluoro-phenylamine (520 mg, 1.7 mmol, 1 equiv) was dissolved in DCE (15 mL). To this solution was transferred a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (598 mg, 2.07 mmol, 1 equiv.) in DCE (5 mL). To this clear solution was then added acetic acid (372 mg, 6.21 mmol, 3 equiv) in DCM (2 mL), followed by addition of powder NaBH(OAc)3 (1.31 g, 6.2 mmol, 3 equiv.) in one portion under N2 at rt. The yellowish milky solution was stirred at rt overnight. The reaction was diluted with DCM (10 mL) and quenched with 10 mL of aqueous NaHCO3. The two layers were separated, and the aqueous layer was extracted with DCM (10 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), brine (15 mL), dried (anhydrous potassium carbonate), filtered, and concentrated to obtain the title compound as a liquid and was used in next step without further purification.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[CH:11]1([CH2:14][C:15](Cl)=[O:16])[CH2:13][CH2:12]1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][N:34]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>>[CH2:25]([NH:24][C:22](=[O:23])[C:21]1[CH:32]=[CH:33][N:34]=[C:19]([NH:18][C:15](=[O:16])[CH2:14][CH:11]2[CH2:13][CH2:12]2)[CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Reactant: O=C(Cl)CC1CC1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(CC1CC1)Nc1cc(C(=O)NCc2ccccc2)ccn1
Yield: 57 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 2-cyclopropylacetyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(2-cyclopropylacetamido)isonicotinamide was obtained as a colorless solid in 57% yield: 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.48 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.53 (dd, J=5.1, 1.4 Hz, 1H), 7.31-7.24 (m, 5H), 6.87 (br s, 1H), 4.60 (d, J=5.8 Hz, 2H), 2.31 (d, J=7.2 Hz, 2H), 1.08-0.99 (m, 1H), 0.70-0.62 (m, 2H), 0.25 (q, J=4.9 Hz, 2H); MS (ES+) m/z 310.6 (M+1).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[NH:5]=C=O.N[C:9]([NH:11][C:12](N)=[O:13])=[O:10]>>[NH:1]1[C:12](=[O:13])[NH:11][C:9](=[O:10])[NH:4][C:2]1=[O:3].[NH3:5]
Reactant: NC(N)=O
Reactant: NC(=O)NC(N)=O
Reactant: N=C=O
Product: N
Product: O=c1[nH]c(=O)[nH]c(=O)[nH]1

Procedure:
The selective control over pH may be accomplished using any of a variety of well-known buffering systems known in the art. One such buffering system utilizes urea thermal decomposition (i.e., pyrolysis) to increase pH to the desired value. The pyrolysis of urea is well known, and has been described in, for instance, Study of the Urea Decomposition (Pyrolysis) Reaction and Importance to Cyanuric Acid Production, Peter M. Shaber, et al., American Laboratory (August 1999), which is incorporated herein in its entirety by reference thereto for all purposes. For instance, to initiate the pyrolysis reaction, urea is first heated to its melting point of approximately 135° C. With continued heating to approximately 150° C., the urea is vaporized (Eq. 1) and is then decomposed into ammonia and isocyanic acid (Eq. 2). The urea also reacts with the isocyanic acid byproduct to form biuret (Eq. 3). H2N—CO—NH2(m)+heatH2N—CO—NH2(g)  (1) H2N—CO—NH2(g)+heatNH3(g)+HNCO(g)  (2) H2N—CO—NH2(m)+HNCO(g)H2N—CO—NH—CO—NH2(s)  (3) Upon further heating, e.g., to about 175° C., the biuret referenced above reacts with isocyanic acid to form cyanuric acid and ammonia (Eq. 4), as well as ammelide and water (Eq. 5). H2N—CO—NH—CO—NH2(m)+HNCO(g)CYA(s)+NH3(g)  (4) H2N—CO—NH—CO—NH2(m)+HNCO(g)ammelide(s)+H2O(g)  (5) As the temperature is further increased, other reactions begin to occur. For instance, biuret may decompose back into urea and isocyanic acid. The urea produced is unstable at higher temperatures, and thus, will further decompose into ammonia and isocyanic acid. Urea and the byproducts of the pyrolysis reaction will continue to react and further decompose as the reaction mixture is heated.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[C:36]([O:39][CH3:40])=[N:37][CH:38]=1.CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:33]3[CH:38]=[N:37][C:36]([O:39][CH3:40])=[C:35]([NH:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: COc1ncc(Br)cc1NS(C)(=O)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Reaction time: 0.23 h
Yield: 6.7 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (200 mg, 0.356 mmol), N-[5-bromo-2-(methyloxy)-3-pyridinyl]methanesulfonamide (120 mg, 0.428 mmol) and Pd(PPh3)4 (41 mg, 0.036 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 mins. The reaction mixture was passed through a 1 g silica cartridge (pre-conditioned with methanol), washing with methanol. The solvent was removed by blow down. The residue was dissolved in DCM and purified on the ISCO companion, using a 40 g Si cartridge, a gradient of 0-6% methanol in DCM containing 1% ammonia, over 14 mins and a 40 ml/min flow rate. LCMS showed still not pure, therefore the material was further purified by MDAP (Method E). The purified material was dissolved in IPA (3 ml) and 2M NaOH (aq, 3 ml) was added. The reaction mixture was left overnight then concentrated and acidified with 2M HCl (aq). The precipitate was filtered, re-dissolved in methanol and dried by blow down to afford the title compound (11 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[CH:16]=[C:15]([CH3:17])[S:14][C:5]=2[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.C(#N)C.O.[CH3:22][N:23]1[CH2:28][CH2:27]N[CH2:25][CH2:24]1>>[CH3:17][C:15]1[S:14][C:5]2[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:3]([N:2]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:4]=2[CH:16]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2-methyl-10H-thieno[2,3-b][1,5] benzodiazepine hydrochloride (100 g) is taken in N-methyl piperazine (500 ml). Reaction mixture is heated at 120° C. for 3 hours. The reaction mass is cooled and acetonitrile (400 ml) is added under stirring for 30 minutes. Water (500 ml) is added and the mixture is cooled up to room temperature and stirred to precipitate the solid. The solid is filtered off, washed with acetonitrile (100 ml) and dried at ambient temperature to obtain the crude title compound (64 g).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[N:5]([C:9]([CH:25]3[CH2:27][CH2:26]3)=[N:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:6]=[CH:7][N:8]=1>O.CC(O)CC>[CH:25]1([C:9]2[N:5]3[CH:6]=[CH:7][N:8]=[C:3]([NH2:1])[C:4]3=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[N:10]=2)[CH2:27][CH2:26]1
Reactant: N
Reactant: Clc1nccn2c(C3CC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: O
Solvent: CCC(C)O
Product: Nc1nccn2c(C3CC3)nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h

Procedure:
A solution of NH3 in H2O (20 M, 2 mL) was added to a suspension of 8-chloro-3-cyclopropyl-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazine (33 mg, 0.091 mmol) in 2-butanol (0.4 mL). The mixture was heated in an oil bath set at 105° C. overnight. Reaction mixture was concentrated in vacuo and purification by prep TLC (4% MeOH in DCM as eluent) afforded the title compound as a solid. 1H NMR (400 MHz, CDCl3): δ 0.95-1.22 (m, 4H), 1.93-2.09 (m, 1H), 5.10 (br. s., 2H), 7.02-7.18 (m, 6H), 7.32-7.44 (m, 3H), 7.55-7.62 (m, 2H). MS (ES+): m/z 343.15 (100)[MH+]. HPLC: tR=2.52 min (Open Lynx polar—5 min).