Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:53]=[N+:54]=[N-:55])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[N:53]([C@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][CH2:9][C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])[CH2:4][CH2:3]1)=[N+:54]=[N-:55]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](CO[C@H]1CC[C@@H](O)CC1)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](CO[C@H]1CC[C@H](N=[N+]=[N-])CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl {(1S)-2-[(cis-4-hydroxycyclohexyl)oxy]-1-methylethyl}carbamate (5.00 g), triphenylphosphine (7.20 g) and diphenylphosphorylazide (5.03 g) in toluene (200 mL) was added dropwise a solution (1.9 M, 14.4 mL) of diisopropyl azodicarboxylate in toluene, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was suspended in diethyl ether, and the precipitate was removed by filtration. The filtrate was concentrated, and the residue was purified by silica gel chromatography(hexane/ethyl acetate) to give the title compound (1.05 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5]([CH3:15])=[CH:4][N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[C:5]([CH3:15])=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)=[CH:30][CH:29]=3)[N:7]=2)=[CH:9][CH:10]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1ccc(F)cc1
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1ccc(F)cc1
Yield: 79 %

Procedure:
The title compound was prepared according to procedure B from 2-chloro-4-(4-fluorophenyl)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 79% yield (yellow solid) after purification by flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H), 7.63 (m, 2H), 7.55 (d, 2H, J=8.5 Hz), 7.22 (t, 2H, J=8.7 Hz), 7.14 (t, 2H, J=8.7 Hz), 3.44 (s, 2H), 2.42 (bs, 8H), 2.25 (s, 3H), 2.24 (s, 3H); MS (ESI): 392.0 [M+H]+, 196 [M+H]2+.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH3:10][CH:11](O)[CH2:12][CH2:13][CH3:14].[S:16]([Cl:19])([Cl:18])=[O:17].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>[Cl-].[Zn+2].[Cl-].Cl>[Cl:3][CH:11]([CH2:12][CH2:13][CH3:14])[CH3:10].[S:16]([Cl:19])([Cl:18])=[O:17].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3]
Reactant: CCCC(C)O
Agent: Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCC(C)Cl

Procedure:
Methods of preparing isomerically pure alkyl chlorides are known and described in the literature. S. R. Sandler, J. Org. Chem. 35, 3967 (1970), describes the conversion of primary, secondary and tertiary alcohols into alkyl chloride compounds by reacting the alcohols with an excess of cyanuric chloride under anhydrous conditions. Furthermore, on page 3968 of the text, the reaction of 2-pentanol with cyanuric chloride, zinc chloride/hydrogen chloride, thionyl chloride/pyridine and with hydrogen chloride is described. Isomerically pure 2-chloro-pentane is obtained in a yield of 48% in the reaction with thionyl chloride/pyridine and in a yield of 57% in the reaction with cyanuric chloride alone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C=O.F[C:17](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.CCOCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[CH2:17])[CH2:7][CH2:6]2
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1CCc2cc(OC)ccc2C1=O

Procedure:
A mixture of 6-methoxytetralone (29.24 g, 165.9 mmol), paraformaldehyde (22.4 g, 746.6 mmol) and N-methylanilinium trifluoroactate (55 g, 248.9 mmol) in 250 mL THF was refluxed for 4 hours and allowed to come to room temperature. To this was added ether (250 mL) with stirring and the mixture was decanted to remove the gummy precipitate. The supernatant was washed with sat. NaHCO3, the oganic layer was dried (MgSO4) and concentrated. The residue was redissolved in ether, filtered through celite and concentrated to afford the title compound as a thick yellow oil.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)=[N+]=[N-].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:11]([O:10][C@@H:8]1[C@H:7]2[CH2:18][O:19][C@H:5]([O:6]2)[C@H:4]([N:1]2[C:23](=[O:24])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:25])[CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reactant: O=C1OC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reaction time: 360 h
Yield: 14.3 %

Procedure:
1,6-Anhydro-2-azido-4-O-benzyl-2,3-dideoxy-β-D-ribo-hexoyranose (see Example 13) (1.0 g), phthalic anhydride (0.74 g), triphenylphosphine (1.21 g) and tetrabutylammonium cyanide (0.1 g) were heated under reflux in a nitrogen atmosphere in benzene (50 ml) for 40 h. Methanol (10 ml) was then added and the solution was allowed to stand at room temperature for 15 days. The solution was then evaporated and the residue was chromatographed on silica gel to yield the title compound as a crystaline solid (0.2 g, 14%) from amongst a variety of products (t.l.c.evidence). Recrystallised from ethanol it had m.p. 135°-136° C., [α]D -28.4°; 13C-nmr data: 100.4 (C-1), 51.1 (C-2), 25.0 (C-3), 76.5 and 75.7 (C-4 and C-5), 67.4 (C-6), 70.4 (PhCH2O), 167.7 (C=0), 156.0 and 131.8 (q-aromatic), 134.0, 128.3, 127.6, 127.5 and 123.3 (aromatic).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[NH:13][N:12]=[C:11]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])([O-:3])=[O:2].Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]([CH3:21])[N:13]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:12]=[C:11]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])([O-:3])=[O:2]
Reactant: CCOC(=O)C1=NNC(C)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: ClCCN1CCOCC1
Product: CCOC(=O)C1=NN(CCN2CCOCC2)C(C)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]

Procedure:
This compound is prepared using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-nitrophenyl)-6-methyl-3,5-pyridazine dicarboxylate and N-(2-chloroethyl)morpholine.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)[CH2:8][CH2:9][NH:10][CH3:11])(C)(C)C.Cl[C:24]1[S:28][N:27]=[C:26]([N:29]2[CH:33]=[CH:32][N:31]=[CH:30]2)[N:25]=1.O>CS(C)=O.CCOC(C)=O>[O:17]1[C:16]2[CH:20]=[CH:21][C:13]([CH2:12][NH:7][CH2:8][CH2:9][N:10]([C:24]3[S:28][N:27]=[C:26]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)[N:25]=3)[CH3:11])=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: CNCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Reactant: Clc1nc(-n2ccnc2)ns1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CN(CCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-(2-methylamino-ethyl)-carbamic acid tert-butyl ester (200 mg, 649 μmol), 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole (121 mg, 649 μmol) and TEA (181 μL, 1.30 mmol) in DMSO (6 mL) was stirred at r.t. for 21 h. Water (50 mL) was added and the solution was extracted with ethyl acetate (2×25 mL), washed with brine, dried over Na2SO4, filtered and concentrated to a clear oil. The crude residue was dissolved in TFA/DCM (1:1, 4 mL) and stirred at room temperature for 30 min. The solvent was evaporated to afford an orange oil. The crude product was diluted with EtOAc (50 mL), washed with 1M NaOH (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to an oil. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 21.3 mg (9%) of N′-benzo[1,3]dioxol-5-ylmethyl-N-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-N-methyl-ethane-1,2-diamine as a white solid. [M+H]+ 358.92; 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.64 (s, 1H), 7.07 (s, 1H), 6.81 (s, 1H), 6.73 (m, 2H), 5.92 (s, 2H), 3.76 (s, 3H), 3.65 (br s, 1H), 3.14 (m, 4H), 2.95 (t, 2H).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][N:18]=[C:19]([N:20]3[CH2:25][CH2:24][CH2:23][CH:22]([NH:26][C:27](=O)[O:28][C:29](C)([CH3:31])[CH3:30])[CH2:21]3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl>O1CCOCC1>[C:15]([N:16]=[C:27]([O:28][C:29]1[CH:31]=[CH:10][CH:4]=[CH:5][CH:30]=1)[NH:26][CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:19]2[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:21]1)#[N:11]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(NC(=O)OC(C)(C)C)C4)ncnc32)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CCCC(NC(=NC#N)Oc5ccccc5)C4)ncnc32)cc1
Temperature: 25 °C

Procedure:
To a solution tert-butyl 1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-ylcarbamate (6.3 g, 20 mmol) in dioxane (50 ml) was added 4.0 N HCl (50 mL, 200 mmol) and stirred at rt. After several hours, the reaction mixture was concentrated in vacuo to give the deprotected amine. A solution of 1-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (580 mg, 1.29 mmol) and diphenyl cyanocarbonimidate (370 mg, 1.5 mmol) in DMF (20 mL) was heated at 65 C for 16 h. the reaction mixture was cooled to rt and diluted with EtOAc and water (1:2, 200 mL). The organic phase was separated washed subsequently with sat. NaHCO3 brine, water, dried (Na2SO4) and concentrated in vacuo to afford 155.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45][CH2:44]1>>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([N:43]3[CH2:48][CH2:47][S:46](=[O:50])(=[O:49])[CH2:45][CH2:44]3)=[O:30])[C:24]=2[CH:33]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S1(=O)CCNCC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)N4CCS(=O)(=O)CC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: Ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and thiomorpholine 1,1-dioxide
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3[N:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15]([OH:17])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH2:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:24]([OH:28])[C:25]([NH2:27])=[O:26]>>[NH2:27][C:25](=[O:26])[CH:24]([OH:28])[CH:23]([NH:22][C:15](=[O:17])[C:14]1[CH:18]=[CH:19][CH:20]=[N:21][C:13]=1[C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)c1cccnc1-c1nc(-c2ccc(F)cc2)cs1
Product: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-c1nc(-c2ccc(F)cc2)cs1
Yield: 93.9 %

Procedure:
Coupling of 2-(4-(4-fluorophenyl)thiazol-2-yl)nicotinic acid (356 mg, 1.185 mmol) and 3-amino-2-hydroxy-4-phenylbutanamide (280 mg, 1.442 mmol) in an analogous manner as described for example 1.2 afforded 530 mg of the title compound as white amorphous solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]([CH:22]2[CH2:24][CH2:23]2)[C:19](=[O:21])[CH3:20])=[CH:10][CH:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].ClCCl.O>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11]([N:18]([CH:22]2[CH2:24][CH2:23]2)[C:19](=[O:21])[CH3:20])[CH2:10][C@@H:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(C1=CC(C)N(Cc2ccccc2)c2ccccc21)C1CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: O
Product: CC(=O)N(C1CC1)[C@@H]1C[C@H](C)N(Cc2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
To a solution of N-(1-benzyl-2-methyl-1,2-dihydro-quinolin-4-yl)-N-cyclopropyl-acetamide (7.5 g) in methanol (160 ml) and tetrahydrofuran (375 ml), nickel chloride hexahydrate (5.4 g) was added. After cooling at 0° C., sodium borohydride (3.41 g) was added in small portions, and then the mixture was stirred at room temperature overnight. Dichloromethane and water were added to the mixture. The organic layer was separated and the solvent was removed under reduce pressure. The crude compound was purified by flash chromatography on silicagel using cyclohexane/methanol (90/10), then (80/20), then (70/30) to give the Cis-N-(1-benzyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-cyclopropyl-acetamide (3.9 g, 51.7% yield).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH:14]([CH2:16][CH2:17][CH3:18])[CH3:15]>C(O)C>[CH2:11]([O:10][C:2](=[O:9])[CH:3]([CH:14]([CH3:15])[CH2:16][CH2:17][CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC(C)Br
Agent: [Na]
Solvent: CCO
Product: CCCC(C)C(C(=O)OCC)C(=O)OCC
Yield: 67.4 %

Procedure:
Sodium metal (5.24 g, 0.23 g atm) was reacted with 25 mL of absolute ethanol. To this solution was added dropwise, with stirring, diethyl malonate (36.0 mL, 0.24 mol). The solution was heated to reflux and 2-bromopentane (29.0 mL, 0.23 mol) was added dropwise. After refluxing overnight, the reaction was cooled and the ethanol removed on a rotovap. The product was washed with water, dried with MgSO4 and fractionally distilled to give 35.7 g of the desired product.
Reaction SMILES: CN(C)C=O.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])(=O)C.S(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[C:11]([O:21][CH3:22])[CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1O
Temperature: 25 °C
Yield: 92 %

Procedure:
Dimethylformamide (0.5 ml) was added to a solution of 7-(acetoxy)-6-methoxyquinazolin-4-(3H)-one (2.0 g, 8.5 mmol) in thionyl chloride (32 ml) and the reaction mixture was heated at reflux for 1.5 hours. Upon cooling to ambient temperature, the thionyl chloride was removed in vacuo and azeotroped twice with toluene. The residue was diluted with dichloromethane (15 ml), a solution of 10% ammonia in methanol (80 ml) added and the mixture heated at 80° C. for 10 minutes. Upon cooling to ambient temperature, the solvent was evaporated to almost complete dryness, water was added and the pH adjusted to 7 with dilute hydrochloric acid. The resultant precipitate was collected by filtration and dried in vacuo at 35° C. for 18 hours to yield 4-chloro-7-hydroxy-6-methoxyquinazoline (1.65 g, 92% yield):
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])[CH2:6][CH2:5]2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[CH:35])=[N:32][CH:33]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]#[C:35][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:12])[CH2:6][CH2:5]4)=[N:32][CH:33]=2)=[CH:26][CH:27]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=C(OCCN1CCCC1)N1CCc2cc(I)ccc21
Product: O=C(OCCN1CCCC1)N1CCc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc21

Procedure:
Prepared according to general working method I from 2-pyrrolidin-1-yl-ethyl 5-iodo-2,3-dihydro-indole-1-carboxylate (120 mg, 0.31 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (80 mg, 0.37 mmol).
Reaction SMILES: C=O.[CH2:3]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([N:18](C)C)=[N:9]1)=[O:7])[CH3:4]>C(O)=O>[CH2:3]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([NH2:18])=[N:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)n1nc(N(C)C)c2ccc(Cl)cc21
Agent: C=O
Solvent: O=CO
Product: CCOC(=O)n1nc(N)c2ccc(Cl)cc21

Procedure:
Analogously to Example 49, 0.1 mol of 3-amino-6-chloroindazole-1-carboxylic acid ethyl ester and 0.25 mol of 40% strength formaldehyde solution in 150 ml of formic acid give 3-dimethylamino-6-chloroindazole-1-carboxylic acid ethyl ester (melting point: 98°-100° C; 69% of theory) in 5 hours at 100° C.
Reaction SMILES: B#B.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]>C1COCC1>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: B#B
Solvent: C1CCOC1
Product: NCc1ccc(N)c([N+](=O)[O-])c1

Procedure:
One equivalent of diborane in THF was added to a solution of 1-amino-2-nitro-4-cyanobenzene (500 mg.) in anhydrous THF (20 ml.) under nitrogen at 10°. After 2 hours excess diborane was destroyed by addition of MeOH and the reaction mixture was evaporated to dryness. The residue was dissolved in methanol and methanolic HCl added. The solvent was evaporated, the residue was basified and the product extracted with ether (x3). The combined extracts were dried and evaporated to give impure 1-amino-2-nitro-4-aminomethylbenzene. To a solution of this diamine (350 mg.) in dry dioxan (10 ml.) was added "Boc-On" (Aldrich Chemical Co.) (258 mg.). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated, and the residue purified by chromatography on silica using CH2Cl2 /ether as eluant. There was thus obtained 1-amino-2-nitro-4-(t-butoxycarbonylaminomethyl)benzene. This product was hydrogenated at ambient pressure in THF/ethanol solution using 10% w/w palladium-on-carbon catalyst to give 1,2-diamino-4-(t-butoxycarbonylaminomethyl)benzene which was used without further purification.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Cl-].[Na+].O>[CH2:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)CCCN2
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc(CN2CCCc3ccccc32)cc1
Temperature: 120 °C

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (0.5 g, 3.75 mmol), benzyl bromide (0.67 mL, 5.63 mmol) and diisopropylethyl amine (0.98 mL, 5.63 mmol) in DMF (5 mL) was heated in an oil bath (T˜120° C.) for 16 hours. Reaction mixture was cooled, added to brine (75 mL) and extracted with ethyl acetate (100 mL). Organic layer was washed with brine (4×) and decolorized with activated charcoal. Upon filtering, it was dried with MgSO4, filtered again and evaporated to dryness to provide Compound 5 as an oily residue (420 mg) with the structure given below:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[H-].[Na+].C([Li])(C)(C)C.CN(C)[CH:21]=[O:22]>O1CCCC1>[F:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH:21]=[O:22])[CH:3]=1)[NH:9][N:8]=[CH:7]2
Reactant: Fc1cc(Br)c2[nH]ncc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc2cn[nH]c12
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 112.1 %

Procedure:
To a solution of 7-bromo-5-fluoro-1H-indazole (1.66 g, 7.72 mmol) in tetrahydrofuran (35 mL) at 0° C. was added sodium hydride (0.618 g, 15.4 mmol). The ice bath was removed and stirring continued for 20 min. The solution was cooled to -78° C. and treated with tert-butyllithium (1.7 M in pentane, 9.08 mL, 15.4 mmol) dropwise. The reaction was stirred at −78° C. for 10 min, allowed to warm gradually in the dewar to −50° C., recooled to −78° C., and then treated with dimethylformamide (2.39 mL, 30.9 mmol). After 15 min, the ice bath was removed and stirring continued for 1 h. The reaction was poured onto ice/I M hydrochloric acid (26.5 mL). The mixture was extracted with ethyl acetate (2×). The organics were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.42 g of 5-fluoro-1H-indazole-7-carbaldehyde (quant.) as a light yellow solid. LC/MS (HPLC method 3): tR=1.39 min, 165.17(MH)+.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=[C:8]([CH3:15])[N:7]=1>CO>[CH3:1][O:13][C:12]([C:11]1[C:6]([OH:5])=[N:7][C:8]([CH3:15])=[CH:9][CH:10]=1)=[O:14]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)O)c(O)n1
Solvent: CO
Product: COC(=O)c1ccc(C)nc1O
Yield: 100 %

Procedure:
Acetyl chloride (50 ml) was added cautiously to a stirred suspension of 2-hydroxy-6-methylpyridine-3-carboxylic acid (14.3 g, 93.44 mmol) in dry methanol (500 ml) and the resulting solution was heated to reflux. After 16 h the solution was evaporated in vacuo to give the title compound (15.62 g, 100%) as a solid: 1H NMR (DMSO) shows the methyl singlet at δ 3.71.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([O:34][CH:35]([CH3:37])[CH3:36])[NH2:33]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:29][N:33]=[C:32]([O:34][CH:35]([CH3:37])[CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(C)OC(N)=NO
Product: CC(C)Oc1noc(C2CC(c3ccc(CC(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
According to General Method 1, 150 mg (0.362 mmol) of the compound from Example 58A and 62.7 mg (0.398 mmol, purity 75%) of isopropyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were reacted. Yield: 41.6 mg (23% of theory).