Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>>[C:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:14]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([Cl:30])[CH:17]=3)[NH:8][N:7]=2)[CH2:36][CH2:35]1)(=[O:33])[CH3:32]
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 14 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 14% yield; NMR Spectrum: 1.97 (s, 3H), 1.97-2.01 (m, 2H), 2.31 (t, 2H), 2.38 (t, 2H), 2.45 (t, 2H), 3.33-3.40 (m, 4H), 4.35 (t, 2H), 5.29 (s, 2H), 7.23 (d, 1H), 7.37 (t, 1H), 7.54-7.58 (m, 2H), 7.86-7.90 (m, 2H), 8.27 (s, 1H), 8.45 (br s, 1H), 8.60 (d, 1H); Mass Spectrum: 537 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C(N(CC)CC)C.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(#N)C>[CH3:13][C:4]1[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:3]=1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc2c(c(N3CCCCC3)n1)C(=O)OCC2
Yield: 95 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.265 mmol) was suspended in 8 mL of anhydrous acetonitrile and then dropwisely added with 1.0 mL of triethylamine and piperidine (0.19 mL, 1.898 mmol) in this order and heated to reflux for about 3 hours under the nitrogen atmosphere. The mixture was concentrated under reduced pressure, added with 10 mL of a saturated solution of ammonium chloride and 10 mL of distilled water and then extracted twice with 30 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (10% EtOAc/MC) was performed on the resulting residue and 296 mg (95%)of 6-methyl-8-piperidine-1-yl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[CH3:12][CH:13]([NH2:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][CH:13]([CH3:12])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(N)CCc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1O
Product: Cc1cc(C(=O)NC(C)CCc2ccccc2)ccc1O

Procedure:
Prepared in a similar manner to example 4 using 4-hydroxy-3-methyl-benzoic acid and 1-methyl-3-phenyl-propylamine. MS (M+H, 284.2)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:10](OCCCOC)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: COCCCOC(=O)c1ccc(C)c(OCCCOC)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(CO)ccc1C
Temperature: 25 °C

Procedure:
The solution of 7.70 g of 3-methoxypropyl 3-(3-methoxypropoxy)-4-methylbenzoate in 20 ml of tetrahydrofuran is added dropwise at 20-60° C. to the stirred mixture of 1.02 g of lithium aluminium hydride in 20 ml of tetrahydrofuran. The reaction mixture is stirred at reflux over 3 hours and subsequently cooled to room temperature. 2 ml of water, 2 ml of 2N NaOH and once again 2 ml of water are successively added dropwise. The suspension is stirred at room temperature over 14 hours. The reaction mixture is poured onto 250 ml of 2N HCl (cold) and extracted with ethyl acetate (2×200 ml). The organic phases are washed successively with 2N HCl (100 ml), water (100 ml) and brine (1×100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (1:1 EtOAc-heptane); Rt=3.59.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]([NH:12][CH2:13][CH2:14][NH2:15])(=[O:11])[CH3:10].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:9]([NH:12][CH2:13][CH2:14][NH:15][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)(=[O:11])[CH3:10]
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(=O)NCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NCCNc1ccc(C)nn1
Yield: 57.7 %

Procedure:
A mixture of 3-chloro-6-methylpyridazine (1.29 g, 10 mmol), N-(acetyl)ethylenediamine (638 mg, 6.25 mmol) and NaHCO3 (1.6 g) in dry DMF (10 mL) was heated at reflux under argon for 20 h. The mixture was filtered, the filtrate concentrated, and the residue was dissolved in CH2Cl2 and purified by flash chromatography (silica gel, step gradient, 0-8% CH3OH/CH2Cl2) to yield the title compound as a yellow solid (700 mg, 44%): MS (ES) m/e 195.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:39])([F:38])[CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1>>[F:39][C:19]([F:18])([F:38])[CH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:32][CH2:31]2)=[CH:36][CH:37]=1
Reactant: FC(F)(F)COCCOc1ccc(OC2CCNCC2)cc1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Product: O=C(CN1CCC(Oc2ccc(OCCOCC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 27.6 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 4-(4-(2-(2,2,2-trifluoroethoxy)ethoxy)phenoxy)piperidine (319 mg, 1.0 mmol) as crude materials, 75 mg title compound was generated and yield was 27%.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([SH:14])=[N:12][N:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-n2nnnc2S)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(-n2nnnc2S)c1

Procedure:
1-(3-Methoxyphenyl)-5-mercaptotetrazole was reacted with boron tribromide in methylene chloride to produce 1-(3-hydroxyphenyl)-5-mercaptotetrazole. Colorless Crystal. m.p. 176°-178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=3)=[C:12]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C1COCC1.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]([C:13]2[C:12]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[CH:5]=3)=[C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCCCCCOc1cc(-c2cccc([N+](=O)[O-])c2)c(OCCCCCC)cc1-c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCOc1cc(-c2cccc(N)c2)c(OCCCCCC)cc1-c1cccc(N)c1
Yield: 87.8 %

Procedure:
Into a 500 ml three-necked flask equipped with a stirrer, 1,4-bis(3-nitrophenyl)-3,6-di-hexyloxybenzene 9.0 g (17.3 mmol) and 10 wt % palladium activated carbon (Pd/C) 2 g were introduced and dissolved in 200 ml of THF, and then the resulting mixture was reacted for 24 hours at room temperature while filling hydrogen gas therein. After the reaction was completed, the reaction mixture was dried with anhydrous magnesium sulfate, and then solvent was removed to give white crystal. The crystal was dried in a vacuum oven at 40° C. to give 7.0 g of desired product (yield: 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:9]([CH2:23][N:24]([C:26](=[O:31])[C:27]([Cl:30])([F:29])[F:28])[CH3:25])([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:10][CH:11]([OH:14])CO)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:32])[N:7]([C:9]([CH2:23][N:24]([C:26](=[O:31])[C:27]([Cl:30])([F:28])[F:29])[CH3:25])([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:10][CH:11]=[O:14])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(CC(O)CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C)C(=O)C(F)(F)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(CC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C)C(=O)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
tert-Butyl[1-{[(2-chloro-2,2-difluoroacetyl)-methylamino]-methyl}-1-(3,4-dichlorophenyl)-3,4-dihydroxybutyl]methylcarbamate (323 mg) was dissolved in a mixture solvent of tetrahydrofuran (3 mL) and water (3 mL). Sodium periodate (266 mg) was added thereto, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (291 mg, 96%). The compound was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:15]=4)[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Br:39][CH2:40][CH2:41]Br.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Br:39][CH2:40][CH2:41][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[C:11]([C:30]([NH2:32])=[O:31])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]2)[CH:15]=4)=[CH:3][C:2]=1[Cl:1]
Reactant: NC(=O)c1cc(-c2ccc(O)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Reactant: BrCCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.3 %

Procedure:
A 100 ml round bottom flask was loaded with 3-(3-chloro-4-hydroxyphenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide (49.4 mg, 0.084 mmol, Example 408B), K2CO3 (150 mg, 1.085 mmol), DMF (6 ml) and 1,2-dibromoethane (0.09 ml, 1.044 mmol) and stirred at room temperature for 4.5 hours. The reaction mixture was poured into a separating funnel that was loaded with 100 ml water+citric acid (0.5 M solution in water) (10 ml, 5.00 mmol) and extracted with ethyl acetate. The organic layer was washed with dilute (1+5) aq. NaHCO3 solution, then brine, dried over MgSO4, filtered and evaporated to dryness to give 48.6 mg 3-(4-(2-bromoethoxy)-3-chlorophenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide, which was used without further purification. Estimated purity (from LCMS) ˜90%. MS (ESI) m/e+=576/578/580, m/e−=574/576/578 consistent with isotope pattern for 1 Br and 1 Cl.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=1)=O.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].C[O-].[Na+].Cl>C(O)C.CO>[CH3:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:5]2[CH:4]=[CH:3][N:20]=[C:18]([NH:17][C:15]#[N:16])[N:19]=2)[CH:12]=1
Reactant: N#CNC(=N)N
Reactant: Cc1ccnc(C(=O)C=CN(C)C)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Cc1ccnc(-c2ccnc(NC#N)n2)c1
Yield: 37.5 %

Procedure:
To a suspension of 3-dimethylamino-1-(4-methylpyridin-2-yl)prop-2-en-1-one (0.78 g) and cyanoguanidine (1.38 g) in ethanol (8 ml) was added a solution of sodium methoxide in methanol (28%, 1.49 ml), and the mixture was refluxed for 2 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate and tetrahydrofuran (3:1). The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 75 g, 10% methanol in dichloromethane). The solid obtained was triturated with 2-propanol, filtered and dried to give N-(4-(4-methylpyridin-2-yl)-pyrimidin-2-yl)cyanamide (325 mg).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: CCCCCCl
Agent: [Br-]
Agent: [K+]
Product: CCCCCN1C(=O)C(CCO)Oc2ccccc21
Yield: 32 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 1-chloropentane in 32% yield and isolated as a colorless oil; IR (KBr) 3424, 2956, 2932, 1680, 1500, 1272, 1062, 749 cm-1 ; 1H NMR (CDCl3) δ0.91 (t, J=6.8 Hz, 3H), 1.31-1.38 (m, 4H), 1.66 (br t, J=5.5 Hz, 2H), 2.08-2.29 (m, 2H), 2.59 (br s, 1H), 3.87-3.94 (m, 2H), 4.69 (dd, J=7.3, 5.8 Hz, 1H), 6.92-7.08 (m, 4H); Anal. Calc'd for C15H21NO3 : C, 68.42; H, 8.04; N, 5.32. Found: C, 68.10; H, 7.88; N, 5.32.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C@@H:11]1([NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH2:17]>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:17][C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:11]2[NH2:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1N
Reactant: N[C@@H]1CCCC[C@@H]1N
Product: N#Cc1ccc(N[C@@H]2CCCC[C@@H]2N)cc1N
Temperature: 100 °C
Reaction time: 16 h

Procedure:
2-Amino-4-fluorobenzonitrile (200 mg, 1.47 mmol) and cis-cyclohexane-1,2-diamine (839 mg, 7.35 mmol) (Sigma-Aldrich; CAS: 1436-59-5) were added to a vial. The vial was then sealed and heated at 100° C. After 16 hours, the reaction mixture was cooled to room temperature and purified directly by silica gel chromatography (10-100% (10% methanol in DCM)/hexanes, linear gradient) to afford rel-2-amino-4-{[(1R,2S)-2-aminocyclohexyl]amino}benzonitrile. MS ESI calc'd. for C13H19N4 [M+H]+ 231. Found 231. 1H NMR (500 MHz, DMSO-d6) δ 6.97 (d, J=8.6 Hz, 1H), 5.97 (d, J=8.6 Hz, 1H), 5.89 (d, J=1.8 Hz, 1H), 5.85 (d, J=7.7 Hz, 1H), 5.48 (s, 2H), 3.32-3.19 (m, 1H), 3.15 (s, 2H), 3.03-2.90 (m, 1H), 1.64-1.33 (m, 6H), 1.33-1.14 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([CH:8]([C:18]1[CH:26]=[CH:25][C:21]2[O:22][CH2:23][O:24][C:20]=2[CH:19]=1)[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:27]1([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:22]1[C:21]2[CH:25]=[CH:26][C:18]([CH:8]([C:9]3[CH:17]=[CH:16][C:12]4[O:13][CH2:14][O:15][C:11]=4[CH:10]=3)[CH:2]([NH:1][C:34](=[O:35])[CH:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:19][C:20]=2[O:24][CH2:23]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(N)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)C(c1ccccc1)c1ccccc1)C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Reaction time: 2 h
Yield: 70 %

Procedure:
The amino ester of Example 19 (0.510 g, 1.43 mmol) is mixed with diphenylacetyl chloride (0.346 g, 1.5 mmol) in 20 mL of dry chloroform. Triethylamine (0.6 mL, 4.3 mmol) is added to the reaction mixture and it is stirred for 2 hours. The solvent is evaporated and the residue is taken up into 75 mL of ethyl acetate. The solution is washed with 1N hydrochloric acid and saturated sodium bicarbonate respectively. The organic phase is dried (magnesium sulfate), filtered and purified by a short column to afford 0.552 g (70%) of product as a white solid;
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)=[O:4].[CH2:22](Br)[C:23]#[CH:24].[In].Cl>C1COCC1.O.C(OCC)(=O)C>[OH:4][C:3]([C:5]1[NH:9][C:8]2[CH:10]=[C:11]([C:16]([F:17])([F:18])[F:19])[C:12]([C:14]#[N:15])=[CH:13][C:7]=2[N:6]=1)([C:2]([F:20])([F:1])[F:21])[CH2:24][C:23]#[CH:22]
Reactant: C#CCBr
Reactant: N#Cc1cc2nc(C(=O)C(F)(F)F)[nH]c2cc1C(F)(F)F
Agent: Cl
Agent: [In]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C#CCC(O)(c1nc2cc(C#N)c(C(F)(F)F)cc2[nH]1)C(F)(F)F

Procedure:
2-(2,2,2-Trifluoro-acetyl)-6-trifluoromethyl-1H-benzoimidazole-5-carbonitrile (0.31 g; 0.94 mmol), propargyl bromide (80% in toluene; 1.1 mL; 12.3 mmol) and indium (1.08 g; 9.5 mmol) were suspended in THF (12 mL) and 0.03 M HCl (10 mL) and stirred vigorously overnight. The reaction mixture was then diluted with water (60 mL) and ethyl acetate (40 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL) and dried over Na2SO4 to yield a crude material. The crude material was purified by column chromatography (SiO2; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([N+:22]([O-])=O)[C:16]=1[OH:25])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=1[OH:25])(=[O:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Yield: 91.1 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, N-[2-(tert-butoxycarbonylamino)ethyl]-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (200 mg, 0.51 mmol) was reduced with hydrogen and 10% Pd/C (100 mg) to form the desired product (170 mg, 92%). 1H NMR (MeOD-d4): δ 6.84 (m, 2H), 3.15 (t, 2H), 2.95 (t, 2H), 1.42 (s, 9H).
Reaction SMILES: [NH:1]=[C:2]([NH:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])SC.C(N(CC)CC)C.[NH2:24][CH2:25][C:26]1[CH:30]=[N:29][N:28]([CH2:31][C@@H:32]2[C@H:35]([NH:36][C:37](=[O:53])/[C:38](=[N:45]\[O:46][C:47]3([C:50]([OH:52])=[O:51])[CH2:49][CH2:48]3)/[C:39]3[N:40]=[C:41]([NH2:44])[S:42][CH:43]=3)[C:34](=[O:54])[N:33]2[S:55]([OH:58])(=[O:57])=[O:56])[N:27]=1.CN(C=O)C>O1CCOCC1.CCOC(C)=O.O>[NH2:44][C:41]1[S:42][CH:43]=[C:39](/[C:38](=[N:45]/[O:46][C:47]2([C:50]([OH:52])=[O:51])[CH2:49][CH2:48]2)/[C:37]([NH:36][C@@H:35]2[C:34](=[O:54])[N:33]([S:55]([OH:58])(=[O:56])=[O:57])[C@@H:32]2[CH2:31][N:28]2[N:27]=[C:26]([CH2:25][NH:24][C:2](=[NH:1])[NH:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH:30]=[N:29]2)=[O:53])[N:40]=1
Reactant: NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Reactant: CSC(=N)NCCCNC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNC(=N)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)n1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl (3-((imino(methylthio)methyl)amino)propyl)carbamate (32.1 mg, 87 μmol) in dioxane (1 mL, ratio: 2) at rt was added triethylamine (30 μL, 0.22 mmol), 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (example 19, 23 mg, 43 μmol), and DMF (0.5 mL, ratio: 1). After heated to 60° C. for 17 h, the reaction mixture was diluted with EtOAc and water. The aqueous layer was separated, concentrated in vacuo, azeotroped with toluene, and dried on high vac to give the title compound (assumed quantitative). LCMS: Rt=0.51 min, m/z=729.6 (M+1), Method 2m_acidic.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=1)=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:9]([N+:19]([O-:21])=[O:20])[N:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(NC(=O)OCC)nc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1ccc(NC(=O)OCC)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
40 ml of concentrated sulphuric acid are cooled to 8° C. and 5 g of the compound of Stage 1 are added while stirring. At 5° C., 5 ml of concentrated nitric acid are then added dropwise and stirring is continued for 1 hour. Subsequently the mixture is poured on 300 to 400 g of ice and the precipitated crystals are isolated by filtering with suction 4 g of a yellow crystalline compound are obtained. On recrystallizing from ethanol this compound melts at 193° C. 1H-NMR Spectrum: 10.38 (s, NH), 9.72 (s, NH), 8.23 (d, J=9 Hz, 4-H), 8.10 (d, J=9 Hz, 3-H), 4.19d (q, J=7 Hz, OCH2), 4.13 (q, J=7 Hz, OCH2), 1.25 (t, J=7 Hz, CH3), 1.23 (t, J=7 Hz, CH3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11]Br.[C-:13]#[N:14].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][C:13]#[N:14]
Reactant: O=[N+]([O-])c1ccc(Br)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCc1cc([N+](=O)[O-])ccc1Br
Yield: 34 %

Procedure:
A solution of 1-bromo-2-(bromomethyl)-4-nitrobenzene (54 g, 183 mmol) in toluene (200 mL) and water (100 mL) was heated to 60° C., then NaCN (27.2 g, 555 mmol) was added, followed by stirring at reflux overnight. Water was added to the mixture, the aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate=100:1 to 5:1) to give 2-(2-bromo-5-nitrophenyl)acetonitrile (15 g, yield 34%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[N:39]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[N:39]1([CH:45]2[CH2:50][CH2:49][N:48]([CH2:2][CH2:3][CH2:4][S:5]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:22]5[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=6)[CH:21]=5)[NH:16][N:15]=4)[CH2:10][CH2:9]3)(=[O:7])=[O:6])[CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCC(N5CCCCC5)CC4)CC3)n[nH]c12
Yield: 39.2 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-Chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and 4-piperidino-piperidine (187 mg, 1.11 mmol) to afford the title compound (53.14 mg, 39% for 2 steps).