Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:24]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[CH2:30][NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([O:19]CC)=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[CH:5]=1.Cl>C(O)C.O>[F:3][C:4]1[C:24]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[CH2:30][NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:23][C:7]2[C:8]3[C:9](=[O:22])[C:10]([C:17]([OH:19])=[O:18])=[CH:11][N:12]([CH3:16])[C:13]=3[CH:14]=[N:15][C:6]=2[CH:5]=1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(N4CCC[C@H]4CNc4ccccc4)cc3c2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)O)c(=O)c2c3cc(N4CCC[C@H]4CNc4ccccc4)c(F)cc3ncc21
Temperature: 100 °C
Yield: 161 %

Procedure:
3.4 cm3 of 1 N aqueous potassium hydroxide was added, with stirring, to a suspension of 0.66 g of ethyl (S)-8-fluoro-4-methyl-1-oxo-9-(2-phenylaminomethylpyrrolidin-1-yl)-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in 15 cm3 of ethanol and 10 cm3 of water. The mixture was heated at about 100° C. for 24 hours. The suspension obtained was acidified by addition of 3.4 cm3 of 1 N aqueous hydrochloric acid. After cooling, the solid was dewatered and washed three times with 50 cm3 of water and dried at about 100° C. for 4 hours at a pressure of 1 kPa. 1 g of (S)-8-fluoro-4-methyl-1-oxo-9-(2-phenylaminomethylpyrrolidin-1-yl)-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of an orange-colored solid, which melted at around 250° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:11])[CH2:8][CH2:9][OH:10])=[O:6].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:12]=[O:13])[C:5]([N:7]([CH3:11])[CH2:8][CH2:9][OH:10])=[O:6]
Reactant: CN(CCO)C(=O)NCCCl
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(CCO)C(=O)N(CCCl)N=O
Yield: 67 %

Procedure:
0.9 g of 1-(2-chloroethyl)-3-methyl-3-(2-hydroxyethyl)urea is dissolved in 10 ml of acetic acid, and 0.9 g of sodium nitrite is added thereto under stirring. The mixture is stirred at room temperature for one hour. Then, 0.5 g of sodium nitrite is again added to the mixture, and said mixture is further stirred at the same temperature for 4 hours. After the reaction, the mixture is freeze-dried, and the residue obtained is purified by silica gel chromatography (Solvent: chloroform-methanol=10:1). 0.7 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-(2-hydroxyethyl)urea is thereby obtained as a pale yellow oil.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13](Br)[CH:14]=[CH2:15]>CN(C=O)C>[CH2:15]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 93.5 %

Procedure:
To a mixture of potassium phthalimide (310.39 g, 1.68 mol) in DMF (1.0 L) at 0° C. was added allyl bromide (290.4 mL, 3.36 mol) from a dropping funnel over 30 minutes. The reaction was then warmed to room temperature and allowed to stir for 5 days. The mixture was filtered to remove salts while washing the residue with ethyl acetate (1 L), and the filtrate concentrated under reduced pressure. The residue was then partitioned between saturated aqueous NaHCO3 (0.5 L) and CH2Cl2 (0.8 L) and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (2×0.8 L), and the combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give N-allylphthalimide as a white powder (294 g, 94%). 1H NMR (CDCl3) δ 4.30 (d, 2H, J=6.0 Hz), 5.22 (m, 2H), 5.88 (m, 1H), 7.73 (m, 2H), 7.85 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[CH:14][S:13][C:10]=3[C:11]=2[N:12]=1.[C:16]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[N:12]1[C:11]2[C:10]3[S:13][C:14]([C:28]4[CH:29]=[CH:30][C:25]([CH2:24][NH:23][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:26][CH:27]=4)=[CH:15][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: Brc1ccc2c(n1)-c1sccc1CCO2
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cc1

Procedure:
Following Scheme 5, 2-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine and 4-(N-Boc-aminomethyl)-phenylboronic acid were reacted to give tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate. MS: (ESI+)=409.1. Hydrogen chloride in dioxane (4 ml, 4 N) was added to a solution of 67 mg (0.16 mmol) of tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate in 6 ml of methylene chloride and the mixture was stirred for 2 hours. The precipitate was collected, washed with methylene chloride and ethyl ether and dried in vacuum to give 335 (34 mg, 55%). MS: (ESI+) 309.1.
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[N:12]=[C:11]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](=[O:18])[N:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:8]=1[CH3:29])C.Cl.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][NH2:43])=[CH:38][CH:37]=1)#[N:35]>CN(C=O)C>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([N:42]2[C:6]([C:7]3[N:12]=[C:11]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:10](=[O:18])[N:9]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=4)[C:8]=3[CH3:29])=[CH:5][CH:4]=[N:43]2)=[CH:38][CH:37]=1)#[N:35]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCOC(C#Cc1nc(C(=O)N(C)C)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 29.5 %

Procedure:
6-(3,3-Diethoxyprop-1-ynyl)-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.028 g, 0.062 mmol) was dissolved in DMF (1 ml) in a microwave vial. 4-Cyanophenylhydrazine hydrochloride (0.013 g, 0.074 mmol) was added. The vial was sealed and heated with stirring to 120° C. for 5 minutes. The crude mixture was purified on preparative HPLC to give 9 mg (29%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1.COCCOC>O>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:18]=[C:17]3[C:5]([CH2:6][CH2:7][C@@:8]43[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]4)=[CH:4][CH:3]=2)[CH:23]=[N:24][CH:25]=1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cncc(Cl)c1
Solvent: COCCOC
Solvent: O
Product: NC1=N[C@@]2(CCc3ccc(-c4cncc(Cl)c4)cc32)C(F)(F)CO1
Yield: 19 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 5-chloropyridin-3-ylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (19% yield) as a white solid. MS (ISP): m/z=349.8 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Na].[CH3:14][OH:15]>>[CH3:14][O:15][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: CO
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Agent: [Na]
Product: COC(=O)c1cc(C)nc(OC)n1

Procedure:
30.0 g of methyl 2-chloro-6-methylpyrimidine-4-carboxylate are added to a solution of 4.2 g of sodium in 100 ml of methanol. The mixture is heated under reflux for 2 h and concentrated under reduced pressure, and the residue is taken upon in dichloromethane/water. The organic phase is separated off and the aqueous solution is extracted a further five times using dichloromethane. The combined organic extracts are dried over sodium sulfate and the solvent is distilled off under reduced pressure. 25.5 g of methyl 2-methoxy-6-methylpyrimidine-4-carboxylate of melting point 101°-103° C. are obtained in this way.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]>C(Cl)Cl>[CH3:32][O:33][C:34]1[C:35](=[O:58])[C:36]([CH3:57])=[C:37]([CH2:43][C:44]2[CH:45]=[CH:46][C:47]([O:53][C:54](=[O:56])[CH3:55])=[C:48]([CH:52]=2)[C:49]([NH:6][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)=[O:50])[C:38](=[O:42])[C:39]=1[O:40][CH3:41]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 62.6 %

Procedure:
3,5-Bistrifluoromethylaniline (0.368 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.196 g, 0.335 mmol, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[CH2:19]([N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[C:30]([C:31]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:32])=[CH:29][C:28]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1cc(C(=O)Cl)n(Cc2ccccc2)n1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: CC(C)(C)c1cc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)n(Cc2ccccc2)n1
Yield: 39 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1-benzyl-3-tert-butyl-1H-pyrazole-5-carbonyl chloride to afford the title compound (40 mg, 39%). 1H-NMR (δ, ppm, DMSO-d6): 1.29 (s, 9H, t-Bu), 5.67 (s, 2H, CH2), 6.47 (d, 1H, HPy,5, J=6.0 Hz), 6.89 (d, 1H, Harom, J=8.0 Hz), 7.00 (s, 1H, Hpyrrazole), 7.11 (d, 2H, Harom, J=8.0 Hz), 7.22 (t, 1H, Harom, J=7.0 Hz), 7.11 (t, 2H, Harom, J=8.0 Hz), 7.40 (t, 1H, Harom, J=8.0 Hz), 7.48-7.51 (m, 1H, Harom), 7.60 (d, 1H, Harom, J=8.0 Hz), 7.79 (d, 1H, HPy,6, J=6.0 Hz), 10.23 (s, 1H, NHamide), 11.18 (s, 1H, NHPy3), 11.38 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C27H27N6O3: 483.2145; found: 483.2145.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1Br.C([Li])CCC.[F:15][C:16]([F:42])([F:41])[C:17]([NH:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:33])N(C)OC)=[CH:24][N:23]2[C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:18].[NH4+].[Cl-]>C1COCC1>[F:42][C:16]([F:15])([F:41])[C:17]([NH:19][C:20]1[N:21]=[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[CH:24][N:23]2[C:34]=1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:18]
Reactant: Fc1cccc(Br)c1F
Reactant: CON(C)C(=O)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3)n2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3)n2c1)c1cccc(F)c1F
Reaction time: 1.17 h
Yield: 68.4 %

Procedure:
To a solution of 2,3-difluorobromobenzene (471 ml, 4.206 mmol) in dry THF (20 mL) was added a solution of n-butyl lithium (1.6M in hexanes, 2.63 mL) at −78° C. The resulting yellow solution was stirred at the same temperature for 70 minutes, then a solution of 2-trifluoroacetamido-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (0.500 g, 1.28 mmol) in dry THF (20 mL), was added dropwise via a cannula. The red-orange solution was allowed to warm over 60 minutes. Saturated NH4Cl was added and the mixture was stirred for 25 minutes before extracting with EtOAc. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography (CH2Cl2/CH3CN 4/1) to give 390 mg of an orange solid. (69%). MS(FAB), NMR.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=1[O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[C:38]=2[O:45][CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:9][CH:10]=1
Reactant: COCCCOc1c(CCl)cccc1OC
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCOc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cccc1OC

Procedure:
Analogously to Method D, 0.417 g of tertbutyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.278 g of 1-chloromethyl-3-methoxy-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rf=0.17 (1:2 EtOAc-heptane); Rt=6.19.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([N:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH3:20])[CH2:13][CH2:12]2)C1C=CC=CC=1>CO.[Pd]>[CH3:20][N:19]([C:21]1[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=1)[N:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=2)[CH2:15]1
Reactant: CN(c1ccncc1)N1CCc2cc(OCc3ccccc3)ccc2C1
Agent: [Pd]
Solvent: CO
Product: CN(c1ccncc1)N1CCc2cc(O)ccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of 6-benzyloxy-3,4-dihydro-1H-isoquinoline-2-yl-N-methyl-4-pyridinylamine (5.1 g) and 5% palladium-on-carbon (1.0 g) in methanol (75 ml) was shaken on a Parr hydrogenation apparatus at ambient temperature and an initial pressure of 55 psi for 2 hrs. An additional 1 g of catalyst was added, and the mixture was shaken for an additional 4 hrs at an initial pressure of 55 psi. The reaction mixture was filtered through a pad of celite, the pad was washed with methanol, and the filtrate was concentrated to give 3.45 g (92%) of product. Recrystallization from methanol provided the analytical sample, mp 263-266° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC>[CH2:14]([O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C=O)c1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Product: COc1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (5.26 g, 140 mmol) was washed with hexane and the hexane was removed. To the washed sodium hydride was added 75 mL of anhydrous DMF. The resultant slurry was well stirred and 21.38 g (140 mmol) of 2-hydroxy-3-methoxy benzaldehyde (commercially available from Aldrich Chemical Company) was added dropwise, over a period of 45 minutes. The mixture was stirred at 50° C. for 1 h and then 16.2 mL (140 mmol) of benzyl chloride was added in one portion. The reaction mixture was stirred at 50° C. for 3 days and then allowed to slowly (overnight) cool to ambient temperature and the reaction was quenched with 60 mL of 10% aqueous hydrochloric acid solution. The mixture was extracted with 3×250 mL of ethyl acetate and the combined ethyl acetate extracts were washed with 250 mL of aqueous sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with ethyl acetate:hexane (1:9 v/v) to give 26.39 g (77.5%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][N:5]=[CH:4][N:3]=1.[N:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:20]([O:19][C:17]([N:11]1[CH2:12][CH2:13][N:14]([C:2]2[C:7]([O:8][CH2:9][CH3:10])=[CH:6][N:5]=[CH:4][N:3]=2)[CH2:15][CH2:16]1)=[O:18])[CH3:21]
Reactant: CCOc1cncnc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(c2ncncc2OCC)CC1
Temperature: 23 °C
Yield: 65.4 %

Procedure:
A mixture of 4-chloro-5-ethoxypyrimidine (1.98 g, 12.5 mmol), ethyl 1-piperazinecarboxylate (5.93 g, 37.5 mmol) and micropulverized K2CO3 (5.18 g, 37.5 mmol) was heated at reflux in CH3CN (75 mL) for 4 h. Upon cooling to 23° C. the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water (5 mL). The organic phase was dried with anhydrous K2CO3, filtered, and concentrated under reduced pressure. Silica gel chromatography (CH2Cl2 /MeOH;98:2) of the concentrate yielded product (2.29 g, 65%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH3:17])[C:7]2[CH:18]=[CH:19][C:20]([C:22]3[NH:23][CH:24]=[CH:25][CH:26]=3)=[N:21][C:6]1=2)[CH3:4].[C:27](Cl)(=[O:29])[CH3:28].O>CN(C=O)C>[C:27]([N:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[CH:19]=[CH:18][C:7]2[N:8]([CH3:17])[C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]=3[N:5]([CH2:3][CH3:4])[C:6]=2[N:21]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3ccc[nH]3)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3cccn3C(C)=O)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
Sodium hydride (0.013 g, 60% in oil) was added to a solution of 5,11-dihydro-11-ethyl-5-methyl-2-(2-pyrrolyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.100 g) in dry DMF (3 mL) and stirred for 30 min. After cooling to 0° C., acetyl chloride (0.025 g) was added and the reaction mixture was allowed to warm to room temperature overnight. Water was added and the product was extracted with CH2Cl2, dried (anhyd Na2SO4), filtered, and evaporated. The residue was purified by preparative plate chromatography (ethyl acetate/hexanes, 1:1). Crystallization from ethyl acetate/pet ether gave 0.018 g of the title compound, mp 106°-108° C.
Reaction SMILES: NC1N(C)N=CC=1.[CH3:8][N:9]1[C:13]([NH:14][C:15](=S)[SH:16])=[CH:12][CH:11]=[N:10]1>C(N(CC)CC)C>[CH3:8][N:9]1[C:13]([N:14]=[C:15]=[S:16])=[CH:12][CH:11]=[N:10]1
Reactant: Cn1nccc1NC(=S)S
Agent: Cn1nccc1N
Solvent: CCN(CC)CC
Product: Cn1nccc1N=C=S

Procedure:
Using 5-amino-1-methylpyrazole as a starting material, triethylamine salt of 1-methyl-5-pyrazolyldithiocarbamic acid (m.p.: 89° to 94° C.) was synthesized, following the procedures described in Reference Example 1. Ferric chloride was allowed to act upon the resulting product to yield the desired compound. Oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:3](=O)[C:4](=[O:9])[C:5]=1[O:6]CC.[NH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][NH:11][C:3]1[C:4](=[O:9])[C:5](=[O:6])[C:2]=1[NH2:1])[CH3:17]
Reactant: CCOc1c(N)c(=O)c1=O
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNc1c(N)c(=O)c1=O

Procedure:
In the same manner, condensing stoichiometric amounts of 3-amino-4-ethoxy-3-cyclobutene-1,2-dione with ethyl glycinate produces N-(2-amino-3,4-dioxo-1-cyclobutenyl)glycine ethyl ester, m.p. 231°-233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1.FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:28])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Reactant: O=C=Nc1cccc(F)c1
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-fluoro-3-isocyanato-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 377 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.67 (s, 2H) 6.80 (td, J=8.31, 2.37 Hz, 1H) 7.15 (dd, J=8.31, 1.19 Hz, 1H) 7.32 (q, 1H) 7.48 (d, J=8.48 Hz, 2H) 7.53 (t, J=2.37 Hz, 1H) 7.63 (d, J=8.48 Hz, 2H) 7.95 (s, 1H) 8.87 (s, 1H) 8.95 (s, 1H) 8.99 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:12]([NH:20][C:21]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5])=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CNC(=O)c1ccccc1N
Solvent: CCOCC
Product: CNC(=O)c1ccccc1NC(=S)NC(=O)c1ccccc1
Yield: 87.9 %

Procedure:
To a stirred mixture of 12 g of 2-amino-N-methylbenzamide and 200 ml of ether was added dropwise, a solution of 13.1 g of benzoyl isothiocyanate in 100 ml of ether over 30 minutes. The solid was collected, giving 22 g of the desired product as cream-colored crystals, mp 203°-205° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]N1C(=O)CCC1=O>FC(F)(F)S(O)(=O)=O>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C(O)c1cc(I)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.3 %

Procedure:
2-Chloro-4-hydroxybenzoic acid (5.18 g, 30.02 mmol) was dissolved in trifluoromethanesulfonic acid (25 g) and N-iodosuccinimide (6.75 g, 30.00 mmol) was added by portions at 0° C. After stirring at room temperature for 15 hr, trifluoromethanesulfonic acid (25 g) was further added, and N-iodosuccinimide (2.02 g, 8.98 mmol) was added by portions at 0° C. After stirring at room temperature for 13.5 hr, the reaction mixture was added to ice water (300 ml), and the mixture was stirred for 2 hr. The precipitated solid was collected by filtration, washed with water, and vacuum dried to give a mixture (8:2) (5.76 g) of 2-chloro-4-hydroxy-5-iodobenzoic acid and 2-chloro-3,5-diiodo-4-hydroxybenzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.I[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)I
Reactant: Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])c(OC(C)C)c1
Yield: 64 %

Procedure:
A mixture of 23 g (150 mmol) of 5-methyl-2-nitrophenol 28.1 g (1.1×150 mmol) of 2-iodopropane and 22.8 g (1.1×150 mmol) of anhydrous potassium carbonate in 150 ml of acetonitrile is stirred and refluxed for 18 hours overnight. The solids were removed, the solvent evaporated and the residue is taken up in diethyl ether and the solution washed with 50 ml of 2N potassium hydroxide (2X), brine, dried (magnesium sulfate), and evaporated to an oil. Distillation gives 18.6 g (64%) of 5-methyl-1-(1-methylethoxy)-2-nitrobenzene; bp 98°-100° C. at 0.5 mm.