Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:4]=1.[H][H]>CO.[C].[Pd]>[ClH:1].[ClH:1].[NH2:2][C:3]1[N:7]([C:8]([NH2:10])=[NH:9])[N:6]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:4]=1
Reactant: N=C(N)n1nc(-c2ccc([N+](=O)[O-])cc2)cc1N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)n1nc(-c2ccc(N)cc2)cc1N
Yield: 130.3 %

Procedure:
A catalytic amount of 10% palladium-carbon was added to a solution of 0.24 g of 5-amino-3-(4-nitrophenyl)-1H-pyrazole-1-carboxamidine hydrochloride in 40 ml of methanol and stirred for 30 minutes in a hydrogen atmosphere of normal pressure at room temperature. The reaction solution was filtered to remove the insoluble solids therefrom, and 0.5 ml of 4N hydrochloric acid-dioxane were added thereto. The solvents were removed by distillation under reduced pressure, and the resulting residue was recrystallized from ethanol-ether to obtain 0.16 g of 5-amino-3- (4-aminophenyl)-1H-pyrazole-1-carboxamidine dihydrochloride.
Reaction SMILES: ClCI.[Br:4][C:5]1[CH:6]=[C:7]([C:19]([OH:22])=[CH:20][N:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:9].[C:23]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:4][C:5]1[N:21]=[CH:20][C:19]2[O:22][CH2:23][N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[C:8](=[O:9])[C:7]=2[CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(F)cc1)c1cc(Br)ncc1O
Agent: ClCI
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(Br)ncc2OCN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Chloroiodomethane (800 mg, 4.6 mmol) was slowly added to a mixture of 2-bromo-N-(4-fluorobenzyl)-5-hydroxyisonicotinamide (750 mg, 2.3 mmol) and Cs2CO3 (3.0 g, 9.2 mmol) in DMF (20 mL) at 100° C. The mixture was stirred at 100° C. for 2 h. Water was added and the mixture was extracted with EtOAc. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=1:1) to give the product of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[4,3-e][1,3]oxazin-4(3H)-one (600 mg, yield: 80%). 1H-NMR (Methanol-d4, 400 MHz) δ 8.24 (s, 1H), 7.94 (s, 1H), 7.39 (dd, J=5.6, 8.0 Hz, 2H), 7.09 (t, J=8.8 Hz, 2H), 5.34 (s, 2H), 4.75 (s, 2H). MS (M+H)+: 337/339.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Cl:14]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1cccnc1Cl

Procedure:
To the solution of 2-choronicotinic acid (5 g, 31.84 mmol) in dry DCM under nitrogen, Oxalyl chloride (38.21 mmol) and catalytic amount of N,N-dimethylformamide were added carefully with stirring. The reaction was stirred for 3 hr. The solution was concentrated under vacuum to yield 2-chloronicotinyl chloride as solid which was used for next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38][C:39](=[NH:56])[C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[N:45]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43]2>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:56]=[C:39]([C:40]3[CH:41]=[C:42]4[C:46](=[CH:47][CH:48]=3)[N:45]([CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH:44]=[CH:43]4)[N:38]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CCOC(=O)CCn1ccc2cc(C(=N)NO)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Temperature: 80 °C
Yield: 42.9 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (215 mg, 1.05 mmol), EDAC (219 mg, 1.14 mmol) and HOBt (156 mg, 1.14 mmol) in dry DMF (10 ml) were stirred at RT for 10 minutes. Added ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D52) (288 mg, 1.05 mmol) and stirred for 1 hour at RT. Heated at 80° C. for 7 hours. The solution was cooled and EtOAc (50 ml) added. Washed with water (50 ml), sat. sodium hydrogen carbonate (50 ml) and water (50 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from ether to yield 200 mg of the title compound as a very pale pink solid. MS (ES) C25H24N4O4 requires 444; found 445 (MH+)
Reaction SMILES: S(=O)(=O)(O)O.COC(=O)[NH:9][CH2:10][C@H:11]([CH2:16][C:17](=[O:27])N[C@H](C1C=CC=CC=1)C)[CH2:12][CH:13]([CH3:15])[CH3:14].[OH-:29].[Na+]>>[CH3:15][CH:13]([CH2:12][C@H:11]([CH2:10][NH2:9])[CH2:16][C:17]([OH:27])=[O:29])[CH3:14]
Reactant: [OH-]
Reactant: COC(=O)NC[C@H](CC(=O)N[C@@H](C)c1ccccc1)CC(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 117.5 °C
Yield: 40.4 %

Procedure:
A 0.2 l reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120° C. for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25° C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55° C. under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[NH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:15][CH2:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(CCc1c[nH]c2ccc(C#N)cc12)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCc1c[nH]c2ccc(CN)cc12)Cc1ccccc1
Yield: 91 %

Procedure:
A solution of 3-[2-[methyl(phenylmethyl)amino]ethyl]-1H-indole-5-carbonitrile (1.3 g) in dry tetrahydrofuran (100 ml) under nitrogen was treated with lithium aluminium hydride (1.0 g) and heated at reflux for 3 h. Excess lithium aluminium hydride was destroyed with wet tetrahydrofuran, the reaction mixture diluted with ethyl acetate (200 ml), filtered and the filtrate evaporated to dryness to give a pale yellow oil which slowly crystallised to give the title compound as a cream solid (1.2 g) m.p. 84°-5°.
Reaction SMILES: [NH2:1][C:2]1[CH:68]=[CH:67][C:5]([CH2:6][CH:7]2[C:30](=[O:31])[N:29]([CH3:32])[CH:28]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:27](=[O:37])[O:26][CH:25]([CH3:38])[CH2:24][N:23]([CH3:39])[CH:22]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:21](=[O:44])[O:20][CH:19]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([NH2:52])=[CH:48][CH:47]=3)[C:18](=[O:53])[N:17]([CH3:54])[CH:16]([CH2:55][CH:56]([CH3:58])[CH3:57])[C:15](=[O:59])[O:14][CH:13]([CH3:60])[CH2:12][N:11]([CH3:61])[CH:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:9](=[O:66])[O:8]2)=[CH:4][CH:3]=1.[C:69]1(=[O:79])O[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12>C(O)(=O)C>[C:69]1(=[O:79])[N:52]([C:49]2[CH:50]=[CH:51][C:46]([CH2:45][CH:19]3[C:18](=[O:53])[N:17]([CH3:54])[CH:16]([CH2:55][CH:56]([CH3:57])[CH3:58])[C:15](=[O:59])[O:14][CH:13]([CH3:60])[CH2:12][N:11]([CH3:61])[CH:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[C:9](=[O:66])[O:8][CH:7]([CH2:6][C:5]4[CH:67]=[CH:68][C:2]([N:1]5[C:69](=[O:79])[C:70]6=[CH:78][CH:77]=[CH:76][CH:75]=[C:71]6[C:72]5=[O:73])=[CH:3][CH:4]=4)[C:30](=[O:31])[N:29]([CH3:32])[CH:28]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:27](=[O:37])[O:26][CH:25]([CH3:38])[CH2:24][N:23]([CH3:39])[CH:22]([CH2:40][CH:41]([CH3:42])[CH3:43])[C:21](=[O:44])[O:20]3)=[CH:47][CH:48]=2)[C:72](=[O:73])[C:71]2=[CH:75][CH:76]=[CH:77][CH:78]=[C:70]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)CC1C(=O)OC(Cc2ccc(N)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccc(N)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C
Solvent: CC(=O)O
Product: CC(C)CC1C(=O)OC(Cc2ccc(N3C(=O)c4ccccc4C3=O)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN(C)C(CC(C)C)C(=O)OC(Cc2ccc(N3C(=O)c4ccccc4C3=O)cc2)C(=O)N(C)C(CC(C)C)C(=O)OC(C)CN1C

Procedure:
475.6 mg (0.50 mmol) of 8,20-bis-(4-aminobenzyl)-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone (for example from Example 4) were initially charged in 1.5 ml of glacial acetic acid and heated under reflux with 162.9 mg (1.1 mmol) of phthalic anhydride for 5 h. The mixture was concentrated, the residue was taken up in tertbutyl methyl ether (MTBE) and washed with sodium bicarbonate solution and saturated sodium chloride solution. The solution was dried with sodium sulfate, reconcentrated and subsequently filtered over a short silica gel column (Ø=3 cm, l=5 cm) using cyclohexane/ethyl acetate 2:1. Evaporation of the filtrate gave 0.55 g of slightly contaminated 8,20-bis-(4-phthalimidobenzyl)-5,11,17,23-tetraisobutyl-2,4,10,14,16,22-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraaza-cyclotetracosan-6,9,12,18,21,24-hexaone as a yellow foam.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:34]([NH2:36])[CH3:35]>O>[CH2:34]([NH:36][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:35]
Reactant: Oc1ccc2ccccc2c1
Reactant: CCN
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCNc1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
288 parts of β-naphthol, 6.6 parts of triphenyl phosphite and 115 parts of ethylamine gas are heated for 10 hours at 230° C in a pressure autoclave. The pressure is 35 atmospheres. The mixture is added to 2,000 parts of water and the batch is stirred for 30 minutes at 70° - 80° C. The lower oily phase is separated off and distilled. 328 parts of N-ethyl-β-naphthylamine of boiling point 119° - 120° C/0.1 mm Hg are obtained. This corresponds to a yield of 96% of theory.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].[H-].[Na+].[O:30]=[S:31]1(=[O:47])[C:35]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=2[C:33](=[O:41])[N:32]1[CH2:42][CH2:43][CH2:44][CH2:45]Br>>[O:47]=[S:31]1(=[O:30])[C:35]2[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:34]=2[C:33](=[O:41])[N:32]1[CH2:42][CH2:43][CH2:44][CH2:45][N:16]1[CH2:15][CH2:14][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:3][C:2]([F:1])([F:20])[F:21])[C:5]2=[O:19])[CH2:18][CH2:17]1
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Reactant: O=c1n(CC(F)(F)F)c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Product: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCN1CCC(n2c(=O)n(CC(F)(F)F)c3ccccc32)CC1

Procedure:
From 4-(3-(2,2,2-trifluoroethyl)-2-oxo-1-benzimidazolinyl)piperidine [prepared by a modification of Step 2 of Example 1 wherein cesium carbonate replaced the sodium hydride and the reaction was heated at 50° C. for 20 hours] and 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one using the procedures described in Example 1 there was obtained a white solid upon formation of the HCl salt (from methanol and diethyl ether), melting point 237-239° C. Analysis calculated for C25H26ClF3N4O4S.HCl.0.4 H2O: C, 48.85; H, 4.56; N, 9.12; found: C, 48.83 ; H, 4.53 ; N, 9.04. The NMR was consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1[CH2:26][N:27]1[CH2:39][CH2:38][C:30]2[NH:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=3[C:29]=2[C:28]1=[O:40].[H-].[Na+].I[CH3:44]>CN(C=O)C.O.C1COCC1.C(O)(=O)C>[CH3:44][N:31]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=2[C:29]2[C:28](=[O:40])[N:27]([CH2:26][C:3]3[N:4]=[CH:5][NH:6][C:2]=3[CH3:1])[CH2:39][CH2:38][C:30]1=2
Reactant: Cc1c(CN2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,3,4,5-tetrahydro-2[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-1H-pyrido[4,3-b]indol-1-one (261 mg) in dry DMF (25 ml) was treated with sodium hydride (60% dispersion in oil; 30 mg) and the mixture was stirred at room temperature under nitrogen for 15 min. Iodomethane (0.5M solution in DMF; 2 ml) was then added and stirring was continued for a further 15 min. The reaction mixture was then poured into water (100 ml) and the resulting suspension was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water (2×100 ml), dried and concentrated to give a solid. This was dissolved in a mixture of water (10 ml), THF (10 ml) and glacial acetic acid (10 ml) and heated at reflux for 2 h. After cooling, residual THF was removed in vacuo and the remaining solution was basified (to pH14) by addition of 2N sodium hydroxide. The resulting suspension was extracted with ethyl acetate (2×50 ml) and the combined, dried organic extracts were concentrated onto silica (Merck 7385). FCC eluting with System A (100:8:1) gave the title compound (81 mg) as a solid. The 1H-n.m.r. and t.l.c. data obtained for this material were consistent with those obtained for the product of Example 20.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].C1(C)C=CC=CC=1.CO.[H][H]>[Rh].C(O)(=O)C>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: [H][H]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Agent: [Rh]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1cccc(C(O)C2CCNCC2)c1OC
Yield: 96 %

Procedure:
Into a suitable inerted reactor was charged 118 kg (481 mol) of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) as a toluene wet cake and 23.6 kg of 5% rhodium on carbon catalyst at 25° C. To the slurry was then added 850 kg of methanol and 29 kg of glacial acetic acid. The reactor was then pressurized to about 100 psi with hydrogen for about 4-12 hours1 at 40° C. The catalyst was removed by filtration and the reactor and the catalyst were rinsed with 150 kg of methanol.2 The reactor rinse filtrate and the reaction mixture filtrate were combined. The concentration of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) is typically about 10 wt %, affording about 116 kg of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) (96% yield)3. 1A HPLC analysis of the reaction mixture is used to determine that the reaction conversion is at least 98%.2For increase safety, deionized water may be used as a final wash of the catalyst wet cake.3The weight percent of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) and yield are based upon HPLC assay.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[O:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][C:24]([CH:21]1[CH2:22][CH2:23][O:18][CH2:19][CH2:20]1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)c1ccccc1
Reactant: O=C(O)C1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)C1CCOCC1)c1ccccc1
Yield: 99.8 %

Procedure:
Using general procedure E, ((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (616 mg, 2.61 mmol) and tetrahydro-pyran-4-carboxylic acid (339 mg, 2.61 mmol) afforded ((R)-1-phenyl-2-[(tetrahydro-pyran-4-carbonyl)-amino]ethyl)-carbamic acid tert-butyl ester (908 mg, 99%).
Reaction SMILES: C(OC(=O)[NH:7][NH2:8])(C)(C)C.C(O)(=O)C.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([C:23]1[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=1)=O.C1CCN2C(=NCCC2)CC1>CO.C1COCC1>[CH3:30][S:29][C:25]1[N:24]=[C:23]([C:21]2[C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:8][N:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CSc1nccc(C(=O)c2ccccc2F)n1
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CSc1nccc(-c2n[nH]c3ccccc23)n1
Temperature: 25 °C
Yield: 63.7 %

Procedure:
tert-Butylcarbazate (899 mg, 6.8 mmol) and acetic acid (0.5 mL) were added to a mixture of (2-fluoro-phenyl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (840 mg, 3.4 mmol) in MeOH. The resulting mixture was heated at reflux for 16 h; it was then cooled to RT and partitioned between EtOAc and aqueous sodium bicarbonate. The organic layer was separated and dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was placed in a sealed tube with DBU (0.79 mL, 5.3 mmol) and THF. The resulting mixture was heated to 150° C. in a microwave reactor for 30 minutes. The reaction mixture was then evaporated under reduced pressure and the crude residue was purified by flash chromatography (hexane/EtOAc, 4/1) to afford 525 mg of 3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)=[O:6].[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([Cl:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[C:5]([NH:7][C:8]2[CH:9]=[C:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:18])[CH3:19])[CH:11]=[CH:12][CH:13]=2)=[O:6])[C:29]([Cl:33])=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NC(=O)c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
To a solution of tert-butyl {3-[(3-aminobenzoyl)amino]phenyl}carbamate (0.500 g, 1.53 mol) and 2,4,5-trichloropyrimidine (0.25 g, 1.4 mmol) in DMF (3.7 mL) was added potassium carbonate (0.29 g, 2.1 mmol). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with saturated (sat'd) NH4Cl and water. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc twice and the combined organics were washed with water, dried, filtered and concentrated to give 800 mg of crude product, which was purified by Combi-Flash column chromatography (12 g column, 0 to 30% EtOAc in hexane) to give the desired product (66 mg, 10%). LCMS for C22H21Cl2N5O3 (M-tBu+H)+: m/z=420.0, 418.1. 1H NMR (400 MHz, CD3OD): δ 8.26 (s, 1H), 8.11 (t, J=2.0 Hz, 1H), 7.89 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 7.85 (t, J=2.0 Hz, 1H), 7.74 (ddd, J=7.6, 2.0, 0.8 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.32 (dd, J=8.0, 1.2 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.19 (m, 1H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][N-:7][CH2:8][CH2:9][CH3:10].O=P(Cl)(Cl)Cl.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1.[OH-].[Na+].O>ClCCCl>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]=[C:8]([NH:7][CH2:6][CH2:5][O:4][C:3]2[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:2]=2[Cl:1])[CH2:9][CH3:10])=[C:24]([CH3:29])[CH:23]=1
Reactant: CCC[N-]CCOc1ccc(Cl)cc1Cl
Reactant: Cc1cc(Cl)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: CCC(=Nc1ccc(Cl)cc1C)NCCOc1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 65 %

Procedure:
A mixture of 19.5 g (0.075 mole) of N-(2-(2,4-dichlorophenoxy)ethyl)propylamide, 11.4 g (0.075 mole) POCl3 and 250 mls of 1,2-dichloroethane was stirred at 60° C. for six hours. The mixture was cooled to 25° C., whereupon 10.4 g (0.075 mole) of 4-chloro-2-methylaniline was added thereto. An exotherm was noted. The mixture was refluxed for 10 hours and allowed to cool. The product mixture was made basic with a 20% NaOH water solution. The product layer was separated, washed once with 200 ml of water, dried over sodium sulfate, filtered and distilled under reduced pressure to give 65% yield (based on the amide) of the desired product, a thick oil, b.p. 142° C./1.3 mm Hg . NMR confirmed the assigned structure: ##STR4##
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18](SCC)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]=[C:15]3[S:19][C:18]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[N:17][C:16]3=[O:23])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3Cl)c2)S1
Reactant: CN1CCNCC1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4Cl)c3)S2)CC1

Procedure:
5-[1-(2,4-Dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one was prepared from 5-[1-(2,4-dichloro-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1-methyl-piperazine following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[F-].[K+].[I-].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:12]=1
Reactant: O=C1COc2ccc(Br)cc2N1
Reactant: COCCCCl
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)COc2ccc(Br)cc21
Temperature: 100 °C
Reaction time: 40 h

Procedure:
The suspension of 9.87 g of 6-bromo-4H-benzo[1,4]oxazin-3-one [24036-52-0], 9.40 g of 1-chloro-3-methoxypropane, potassium fluoride on alumina (Fluka 60244), 0.144 g of potassium iodide in 500 ml of acetonitrile is stirred at 100° C. over 40 hours. The reaction mixture is cooled to room temperature and filtered through Hyflo, and the filtrate is concentrated by evaporation to dryness. The title compound is obtained as a slightly yellowish solid from the residue by crystallization from ethyl acetate. Rf=0.43 (1:1 EtOAc-heptane). Rt=4.27 (gradient I). m.p. 193-195° C.