Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][N:12]=[CH:11]2)=[CH:5][CH:4]=1)#[N:2].[Br:15][C:16]1[S:17][C:18]([CH2:21]Br)=[CH:19][N:20]=1>>[Br:15][C:16]1[S:17][C:18]([CH2:21][N:9]([N:10]2[CH:11]=[N:12][N:13]=[CH:14]2)[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:19][N:20]=1
Reactant: BrCc1cnc(Br)s1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Product: N#Cc1ccc(N(Cc2cnc(Br)s2)n2cnnc2)cc1

Procedure:
Starting Compounds: 4-(4-cyanophenyl)amino-4H-1,2,4-triazole and 2-bromo-5-(bromomethyl)thiazole
Reaction SMILES: C1(S([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:37])[CH2:27][CH2:26][N:25]([S:28]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)(=[O:30])=[O:29])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=O)=O)C=CC=CC=1.C1COCC1.CO>>[CH3:37][C:22]1([N:17]2[C:18]3[C:14](=[CH:13][N:12]=[C:11]4[C:19]=3[CH:20]=[CH:21][NH:10]4)[N:15]=[N:16]2)[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1
Reactant: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCN(S(=O)(=O)c2cccnc2)CC1
Solvent: CO
Solvent: C1CCOC1
Product: CC1(n2nnc3cnc4[nH]ccc4c32)CCN(S(=O)(=O)c2cccnc2)CC1
Reaction time: 64 h
Yield: 27 %

Procedure:
A mixture of 6-benzenesulfonyl-1-[4-methyl-1-(pyridine-3-sulfonyl)-piperidin-4-yl]-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (74.0 mg, 0.14 mmol) in THF/methanol containing aqueous sodium hydroxide (0.53 mmol) was stirred for 64 hr. The solvent was evaporated under vacuum to a small volume, the residue dissolved in DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum and the resulting residue purified by column chromatography on silica gel (gradient: 0 to 5% [2M NH3 in methanol] in DCM) to afford 15.0 mg (27%) of 1-[4-methyl-1-(pyridine-3-sulfonyl)-piperidin-4-yl]-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. LCMS (Method A, ESI): RT=3.42 min, m+H=398.2; 1H NMR (400 MHz, DMSO): δ 12.45 (s, 1H), 8.99 (s, 1H), 8.86 (m, 2H), 8.13 (ddd, 1H), 7.65 (m, 2H), 6.91 (dd, 1H), 3.49 (m, 2H), 2.90 (m, 2H), 2.75 (m, 2H), 2.31 (m, 2H), 1.75 (s, 3H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([OH:30])[CH2:10][NH:11][CH:12]([CH3:29])[CH2:13][O:14][C:15]2[CH:28]=[CH:27][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[NH:22][C:21]3=[O:26])=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:33]=[O:34]>>[C:1]1([S:7][CH2:8][CH:9]2[O:30][C:33](=[O:34])[N:11]([CH:12]([CH3:29])[CH2:13][O:14][C:15]3[CH:28]=[CH:27][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[NH:22][C:21]4=[O:26])=[CH:17][CH:16]=3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)CSc1ccccc1
Reactant: CN(C)C=O
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)N1CC(CSc2ccccc2)OC1=O

Procedure:
A procedure similar to that described in Example 4 was repeated, except that 1.2 g of 5-{4-[2-(3-phenylthio-2-hydroxypropylamino)propoxy]benzyl}thiazolidine-2,4-dione (prepared as described in Example 37), 0.52 g of N,N'-carbonyldiimidazole and 20 ml of anhydrous dimethylformamide were used, to give 1.15 g of the title compound as a 1:1 mixture of two kinds of diastereomers having an Rf value of 0.30 (polar) and an Rf value of 0.38 (less polar) (on silica gel thin layer chromatography, using a 1:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([O:26]C)=[O:25])=[CH:14][CH:13]=2)[C:9](=[O:28])[C:8]([CH2:29][C:30]#[N:31])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:32].[K+].Cl>>[CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([OH:26])=[O:25])=[CH:14][CH:13]=2)[C:9](=[O:28])[C:8]([CH2:29][C:30](=[O:32])[NH2:31])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [OH-]
Reactant: CCCCc1ccc(CC#N)c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Product: CCCCc1ccc(CC(N)=O)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 3 h

Procedure:
A mixture of 400 mg of 6-butyl-3-cyanomethyl-1-(2'-methoxycarbonylbiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine and 2.2 ml of 1N aqueous KOH solution is boiled for 3 hours, cooled and acidified with hydrochloric acid. 6-Butyl-3-carbamoylmethyl-1-(2'-carboxybiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine is obtained after conventional working-up.
Reaction SMILES: C(O[C:4](=O)[CH:5]([N:9]([CH:23]1[CH2:25][CH2:24]1)[C:10]([NH:12][CH:13]1[CH:20]2[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:22][CH:14]1[CH2:15]3)[CH2:19]2)=[O:11])[CH:6]([CH3:8])[CH3:7])C.[BH4-].[Na+]>C(O)C>[CH:14]12[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:21]3)[CH:13]1[N:12]1[CH:4]=[C:5]([CH:6]([CH3:7])[CH3:8])[N:9]([CH:23]3[CH2:24][CH2:25]3)[C:10]1=[O:11])[CH2:22]2
Reactant: CCOC(=O)C(C(C)C)N(C(=O)NC1C2CC3CC(C2)CC1C3)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1cn(C2C3CC4CC(C3)CC2C4)c(=O)n1C1CC1
Temperature: 55 °C

Procedure:
2-(3-Adamantan-2-yl-1-cyclopropyl-ureido)-3-methyl-butyric acid ethyl ester (110 mg) was dissolved in ethanol (5 mL) under argon and then sodium borohydride (92 mg) was added in one portion. The mixture was heated to 55° C. and stirred over night. TLC analysis confirmed complete consumption of the starting material. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and was then vigorously shaken with 25% HCl. The organic layer was separated, washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography: a first column was eluted with a gradient of methanol in DCM (0 to 5%) and a second column with a gradient of 0 to 10% methanol in DCM/CH3CN (85:15). 1-Adamantan-2-yl-3-cyclopropyl-4-isopropyl-1,3-dihydro-imidazol-2-one was obtained as a colorless oil (23 mg). MS (ESI): 301.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(-c2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)cc1
Yield: 24.2 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.017 g (24%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:18])=[CH:20][CH:21]=2)(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Product: COc1ccc(N(C)S(=O)(=O)c2ccc(C(=O)Nc3ccncc3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (7) (100 mg, 0.31 mmol) was treated with 4-aminopyridine (24 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with 0-70% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 4-(N-(4-methoxyphenyl)-N-methylsulfamoyl)-N-(pyridin-4-yl)benzamide as an off white solid. Yield: 67 mg (65%). 1H-NMR: 10.82 (s, 1H), 8.51 (d, J=6.0 Hz, 2H), 8.12 (d, J=8.5 Hz, 2H), 7.78 (d, J=6.0 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 3.75 (s, 3H), 3.15 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@H](C)[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H]([C@@H](C)CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 17 (470 mg, 1.59 mmol) and 1-bromopentadecane (0.63 mL, 3.18 mmol), alcohol 71 was obtained as a colorless oil (499 mg, 60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:15]1[C:16]2[CH2:24][N:23]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:22][CH2:21][C:17]=2[N:18]=[CH:19][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N>[Cl:31][C:30]1[C:25]([N:23]2[CH2:22][CH2:21][C:17]3[N:18]=[CH:19][N:20]=[C:15]([NH:1][C:2]4[CH:10]=[C:9]5[C:5]([C:6]([CH3:13])([CH3:12])[C:7](=[O:11])[NH:8]5)=[CH:4][CH:3]=4)[C:16]=3[CH2:24]2)=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: Clc1cccnc1N1CCc2ncnc(Cl)c2C1
Reactant: CC1(C)C(=O)Nc2cc(N)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)C(=O)Nc2cc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)ccc21
Reaction time: 1 h
Yield: 80.2 %

Procedure:
A mixture of 6-amino-3,3-dimethylindolin-2-one (156 mg), 4-chloro-6-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (100 mg), and CH3CN (5 mL) was run in a Microwave Reactor at 180° C. for 1 h. After cooling, the mixture was treated with sat. aq. Na2CO3 and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column to give an off-white solid (120 mg, 80%).
Reaction SMILES: [O:1]=[C:2]1[C@H:10]([NH2:11])[CH2:9][CH2:8][C@H:7]2[N:3]1[C@@H:4]([C:12]([O:14]C)=[O:13])[CH2:5][CH2:6]2.[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].C([O-])(O)=O.[Na+].N1CCCCC1.CCN(C(C)C)C(C)C>CC(C)=O.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>[O:1]=[C:2]1[C@H:10]([NH:11][C:16]([O:18][CH2:19][CH:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:9][CH2:8][C@H:7]2[N:3]1[C@@H:4]([C:12]([OH:14])=[O:13])[CH2:5][CH2:6]2
Reactant: COC(=O)[C@H]1CC[C@H]2CC[C@@H](N)C(=O)N21
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: O=C(N[C@@H]1CC[C@@H]2CC[C@H](C(=O)O)N2C1=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
Amino acids were purchased from Advanced Chemtech (Louisville, Ky.), and used as the following derivatives: N-Fmoc-D-Ala-OH.H2O, N-Fmoc-D-Leu-OH, N-Fmoc-D-Glu(O-t-Bu)-OH, N-Fmoc-D-Pro-OH, N-Fmoc-D-Tyr(O-t-Bu), N-Fmoc-D-Arg(Pmc)-OH. (R)-β-hydroxy-N-(Fmoc)valine was prepared from (R)-β-hydroxy-N-(Boc)valine (Dettwiler et al., 2003) by removal of the Boc group (1:1 TFA (trifluoroacetic acid)/CH2Cl2), protection with Fmoc-OSu and NaHCO3 in aqueous acetone (Capatsanis et al. 1983), followed by purification by chromatography over silica gel (1:1:98 MeOH/HOAc/CHCl3) and lyophilization from aqueous acetonitrile (78% yield). (3R,6R,9R)-2-Oxo-3-[N-(Fmoc)amino]-1-azabicyclo[4.3.0]-nonane-9-carboxylic acid was prepared from (3R,6R,9R)-methyl 2-oxo-3-amino-1-azabicyclo[4.3.0]-nonane-9-carboxylate (in turn prepared (Lombart et al. 1996) from D-glutamic acid) by Fmoc-protection with Fmoc-OSu and NaHCO3 in aqueous acetone (Capatsanis et al. 1983), followed by selective hydrolysis of the methyl ester (Pascal et al. 1998). Peptide synthesis was performed on a 0.1 mmol scale (200 mg resin), and conducted by deprotection with piperidine in DMF (10 ml/g resin, 20% v/v, 1×2 min, 1×3 min, 1×10 min) followed by washing with DMF (10 ml/g resin, 5×1 min). Fmoc protected amino acid (0.5 mmol, 500 mol %) dissolved in a solution of TBTU in DMF (0.25 M, 2 ml) was added to the resin. After agitation of the resin (5 min), DIEA (0.6 mmol, 600 mol %) was added, and agitation continued for 1 h. The resin was washed with DMF (10 ml/g resin, 5×1 min), and coupling efficiency determined using the Kaiser test. The resin was agitated using a mechanical vortex apparatus during coupling, rinsing and deprotection sequences. Rp-HPLC analysis was performed on an Alltech C18 column (dimensions 250 mm×4.6 mm) using acetonitrile/water/TFA mixtures, where solvent A=water/0.1% TFA and solvent B=MeCN/0.1% TFA (see below). The flow rate was 0.5 ml/min, and detection was performed at 214 nM.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(N)c1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)c2ccccc2)c1Cl

Procedure:
57 g (0.4 mol) of 2-chloro-3-methyl-aniline [CA 89, 30772h) were dissolved in 1.5 l of toluene, 55 g of potassium carbonate were added and 62 g (0.4 mol) of benzoyl chloride were added dropwise at 80° C. After reaction is complete, the solid was filtered off in the cold and washed with water, and the filtrate was dried. After concentrating and triturating with petroleum ether 98 g of product (100%) crystallized. M.p.: 125°-126° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:12][CH2:13][NH:14][C:15](N1C=CN=C1)=[O:16])[CH3:2]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[C:15](=[O:16])[NH:14][CH2:13][CH2:12][C:4]=12)[CH3:2]
Reactant: CCc1c(CCNC(=O)n2ccnc2)[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: CCc1c2n(c3ccccc13)C(=O)NCC2
Yield: 9 %

Procedure:
A solution of N-[2-(3-ethylindol-2yl)ethyl]-1-imidazolecarboxamide (2.2 g) in toluene (50 ml) was refluxed for 3 hours. After the mixture was evaporated in vacuo, the residue was purified by silica gel column chromatography (5% methanol-chloroform) to give 5-ethyl-3,4-dihydropyrimido[1,6-a]indol-1(2H)-one (0.15 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[CH2:22][C:23](O)=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.N.CC#[N:36]>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:26])[CH2:22][C:23]([NH2:36])=[O:24])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CCN(C(=O)CC(=O)O)CC2)cc1OC1CCCC1
Reactant: CC#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C2CCN(C(=O)CC(N)=O)CC2)cc1OC1CCCC1

Procedure:
In the same manner as Example, 9, 3-[4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-3-oxo-propionic acid (0.70 mmol, 0.25 g), oxalyl chloride (0.77 mmol, 0.385 mL; 2M solution in CH2Cl2), DMF (4 drops) and saturated NH3 /CH3CN solution (10 mL) in dry toluene (10 mL) afforded a solid which was triturated in Et2O/hexane to give the title compound as a white solid, mp=132°-133° C. (0.40 mmol, 0.150 g, 60%).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH:28]([NH:31][S:32]([C:35]1[S:36][C:37]([Cl:41])=[C:38]([NH2:40])[CH:39]=1)(=[O:34])=[O:33])[CH2:29][OH:30]>>[Cl:41][C:37]1[S:36][C:35]([S:32](=[O:34])(=[O:33])[NH:31][CH:28]([CH2:27][OH:26])[CH2:29][OH:30])=[CH:39][C:38]=1[NH:40][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl
Product: O=C(Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.4) according to general procedure II. Light yellow solid. MS (ISP) 624.2 [(M−H)−]; mp 241° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:13]([C:10]2[CH:11]=[CH:12][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:15])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: O=C(O)c1ccn(-c2ccc(F)cc2)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(NC(=O)c2ccn(-c3ccc(F)cc3)c2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.3 %

Procedure:
1-(4-Fluorophenyl)pyrrole-3-carboxylic acid (2 g), 5-amino-2-neopentyloxybenzonitrile (1.8 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.6 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.7 g), melting point: 167–169° C.
Reaction SMILES: ClC(Cl)(Cl)[NH:3][C:4](=[O:17])[NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1.C(=O)(O)[O-].[Na+]>CO.O>[NH:5]([C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=1)[C:4]([NH2:3])=[O:17]
Reactant: CCOC(=O)Cc1csc(NC(=O)NC(Cl)(Cl)Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1csc(NC(N)=O)n1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of ethyl 2-(3-trichloromethylureido)thiazol-4-ylacetate (6.32 g.) in a mixture of methanol (400 ml.) and water (150 ml.) was adjusted to pH 7 to 7.6 with sodium bicarbonate aqueous solution with stirring at room temperature, and then the solution was stirred for 70 minutes at the same temperature. The methanol was distilled off from the reaction mixture under reduced pressure, and the precipitates were collected by filtration, washed with water and then dried to give colorless crystals of ethyl 2-ureidothiazol-4-ylacetate (3.45 g.), mp 173° to 174° C.
Reaction SMILES: [Na].[CH3:2][C:3]1[C:4]([C:9](=O)[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:5][CH:6]=[CH:7][N:8]=1.Cl[CH:17]([C:22](=[N:24][NH:25][S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH3:23])[C:18]([O:20][CH3:21])=[O:19].Cl>CO.C1COCC1>[CH3:23][C:22]1[N:24]([NH:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=2)(=[O:27])=[O:28])[C:9]([C:4]2[C:3]([CH3:2])=[N:8][CH:7]=[CH:6][N:5]=2)=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CC(=O)c1nccnc1C
Reactant: COC(=O)C(Cl)C(C)=NNS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(C(=O)OC)c(-c2nccnc2C)n(NS(=O)(=O)c2ccc(C)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.81 g of sodium was heated with 20 ml of methanol, then a solution of 6.8 g of 31A in 20 ml of methanol was added and the mixture was stirred at room temperature for 1 hour. Then a solution of 11.2 g of 7B in 25 ml of THF was added, and the mixture was stirred at room temperature for 2 hours. The mixture was stripped of volatiles, 100 ml of methanol was added to the residue and hydrogen chloride gas was bubbled through the mixture, which then was heated at reflux for 2 hours. The mixture was cooled, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with methylene chloride. The extract was stripped of volatiles, and the residue was triturated with 10 ml of ether. The solid product was collected and dried (Na2SO4) to give dimethyl 2-methyl-1-(tosylamino)-5-(3-methyl-2-pyrazinyl)pyrrole-3,4-dicarboxylate (31C), as a light yellow solid, m.p.: 177°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4]Br.[CH3:14][C@@H:15]1[C@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][C:17](=[O:26])[NH:16]1>>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][N:16]1[C@H:15]([CH3:14])[C@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:18][C:17]1=[O:26]
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br

Procedure:
Prepared according to the procedure described in Example 6, Step 3, using the following starting materials: 2-bromo-5-(trifluoromethyl)benzyl bromide and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: CO.[F:3][CH:4]([F:45])[O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:44])=[CH:11][C:12](=[O:43])[N:13]2[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH2:32][C:33]3[CH:42]=[CH:41][C:36]4[O:37][CH2:38][CH2:39][O:40][C:35]=4[CH:34]=3)C(=O)OC(C)(C)C)[CH2:20][CH2:19]2)=[CH:8][CH:7]=1.[ClH:46].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:46].[F:45][CH:4]([F:3])[O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:44])=[CH:11][C:12](=[O:43])[N:13]2[CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][CH2:32][C:33]3[CH:42]=[CH:41][C:36]4[O:37][CH2:38][CH2:39][O:40][C:35]=4[CH:34]=3)[CH2:20][CH2:19]2)=[CH:8][CH:7]=1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC(F)F)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC(F)F)ccc12
Reaction time: 1 h

Procedure:
To 1 mL of methanol solution containing 0.16 g of tert-butyl (1-(2-(7-(difluoromethoxy)-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 1 hour. Ethyl acetate was added, and the resulting solid was filtered to give 87 mg of 7-(difluoromethoxy)-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.