Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Br[CH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH:36]6[CH2:39][CH2:38][CH2:37]6)[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: BrC1CCC1
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cnn(C5CCC5)c4)cc32)c1
Yield: 35 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and bromocyclobutane, 147 was obtained as a yellow solid (40 mg, 35%) over two steps. 1H-NMR (500 MHz, CD3OD) δ (ppm): 9.02 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.66-7.69 (m, 1H), 7.25 (d, J=7.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 1H), 4.91-4.96 (m, 1H), 3.90-3.95 (m, 4H), 3.20-3.22 (m, 2H), 3.00-3.02 (m, 2H), 2.52-2.63 (m, 4H), 2.08-2.13 (m, 2H), 1.92-1.99 (m, 2H); MS (ESI) m/z: 415 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=4[C:18]([O:20]CC)=[O:19])=[N:11][N:10]3[CH:27]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=4[C:18]([OH:20])=[O:19])=[N:11][N:10]3[CH:27]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of ethyl 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate (200 mg, 0.54 mmol) in tetrahydrofuran (10 mL) was added 4N aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 3 hr. 6N Hydrochloric acid (1.5 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (130 mg, 73%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:30]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[CH:46]=[CH:45][C:44]([CH2:47]Br)=[CH:43][CH:42]=3)=[N:33][N:32]=[N:31]2)C=CC=CC=1>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:47][C:44]2[CH:45]=[CH:46][C:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[C:34]3[NH:30][N:31]=[N:32][N:33]=3)=[CH:42][CH:43]=2)[C:7]([C:15]#[N:16])=[C:8]([N:10]2[CH:11]=[CH:12][CH:13]=[CH:14]2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(-n2cccc2)c(C#N)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCc1nc(-n2cccc2)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.08 h

Procedure:
A solution of 2-butyl-5-cyano-4-(1H-pyrrol-1-yl)imidazole (Example 8, 1.7 g) in anhydrous tetrahydrofuran (20 mL) was treated with a solution of potassium tert-butoxide (0.97 g) in anhydrous tetrahydrofuran (20 mL) at room temperature. The mixture was stirred for 5 minutes then a solution of N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12, 6.0 g) in anhydrous tetrahydrofuran (20 mL) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 18 hours. The resulting suspension was filtered and the filtrate was evaporated. The residue was purified by flash chromatography on silica gel, eluting with chloroform hexane (90:10) to give the title compound in its triphenylmethyl-protected form. The triphenylmethyl protecting group was removed by refluxing in methanol for 24 hours. Evaporation gave a residue that was purified by chromatography on silica gel, eluting with a gradient of ethyl acetate-hexane (50:50) to ethyl acetate. Evaporation of solvents gave a gum that was redissolved in dichloromethane and evaporated to give the title compound as a solid foam. MS (FAB, thioglycerol) 470 (m+Na-1), 448 (m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[OH:1][C:2]1[C:9]([Br:15])=[CH:8][C:7]([C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([Cl:14])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)c1ccc(O)c(C=O)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(O)c(C=O)c1Cl
Yield: 99.6 %

Procedure:
A solution of 1.97 g (9.26 mmol) of 2-hydroxy-5-(1,1-dimethylethyl)-6-chlorobenzaldehyde and 1.98 g (11.1 mmol) of N-bromosuccinimide in 30 ml of methylene chloride was stirred for 2 hours. Water (50 ml) was added. The organic phase was dried and evaporated. The residue was chromatographed on 150 g of silica gel eluted with 1:99 (v/v) ether:hexane. There was obtained 2.69 g (9.22 mmol, 99%) of 2-hydroxy-3-bromo-5-(1,1-dimethylethyl)-6-chlorobenzaldehyde as a white solid after recrystallization from hexane; mp 103°-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:19]([O-])=[O:20].[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([N:19]=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1(Cc2ccccc2)CCN(N=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a solution of 4-ethoxycarbonyl-4-benzylpiperidine (495 mg) in water (5 mL) was added sodium nitrite (276 mg) and acetic acid (201 μL) and the mixture was stirred at room temperature overnight. To the reaction mixture was added an aqueous saturated sodium hydrogencarbonate solution and the mixture was stirred and extracted with chloroform. The extract was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=85/15 to 80/20) and dried in vacuo to give 4-ethoxycarbonyl-4-benzyl-1-nitrosopiperidine (565 mg, yield: 100%) as a colorless solid. To a solution of the product (565 mg) in methanol (3 mL) was added zinc powder (654 mg) and then added acetic acid (3 mL) under ice-cooling and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added an aqueous saturated sodium hydrogencarbonate solution and chloroform and the mixture was stirred and extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-amino-4-benzyl-4-ethoxycarbonylpiperidine (508 mg, yield: 97%) as a colorless viscidity.
Reaction SMILES: CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH:13](Br)([CH2:15][CH3:16])[CH3:14].[OH:18][C:19]1[C:28]([OH:29])=[C:27]2[C:22]([C:23](=[O:32])[CH2:24][C:25]([CH3:31])([CH3:30])[O:26]2)=[CH:21][CH:20]=1>COCCOCCOC>[CH:13]([O:18][C:19]1[C:28]([OH:29])=[C:27]2[C:22]([C:23](=[O:32])[CH2:24][C:25]([CH3:30])([CH3:31])[O:26]2)=[CH:21][CH:20]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CC1(C)CC(=O)c2ccc(O)c(O)c2O1
Reactant: CCC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CS(C)=O
Product: CCC(C)Oc1ccc2c(c1O)OC(C)(C)CC2=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
In 80 ml of dimethyl sulfoxide 4.2 g (20 millimoles) of 7.8-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 10 ml of diethylene glycol dimethylether, 4.1 g (30 millimoles) of potassium carbonate, 0.5 g of potassium iodide and 3.3 (2.6 ml, 24 millimoles) of sec. butyl bromide are added. The reaction mixture is heated at 100° C. for 10 hours, poured onto 200 ml of crushed ice and extracted with 100 ml of carbon tetrachloride. To the aqueous phase 20 ml of 10% sodium hydroxide solution are added, the mixture is cooled to 0° C., acidified with concentrated hydrochloric acid and stirred at 0° C. for 2 hours. The product is filtered, washed twice with 20 ml of water, dried and crystallized from 20% ethanol. Thus 4.4. g of the desired compound are obtained, yield 83%, mp.: 108°-110° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[N:3]1.Cl.Cl.[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[C:18]([NH:24][CH2:25][CH2:26][NH:27][CH3:28])[CH:17]=[N:16]2>>[F:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[F:23])[N:19]=[C:18]([NH:24][CH2:25][CH2:26][N:27]([CH3:28])[C:7]([C:4]1[C:5]([C:20]3[CH:15]=[CH:14][C:13]([F:12])=[CH:22][CH:21]=3)=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:9])[CH:17]=[N:16]2
Reactant: Cn1ccc(C(=O)O)n1
Reactant: CNCCNc1cnc2cc(F)c(F)cc2n1
Agent: Cl
Product: CN(CCNc1cnc2cc(F)c(F)cc2n1)C(=O)c1nn(C)cc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 4-4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (46 mg, 0.21 mmol) and N-(6,7-difluoro-quinoxalin-2-yl)-N′-methyl-ethane-1,2-diamine.dihydrochloride, D2 (65 mg, 0.21 mmol) according to the procedure described for Example 1, as a yellow solid (65 mg, 71%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:12][CH2:13][CH3:14].[Na+].O>C(O)C>[CH2:13]([O:12][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:14]
Reactant: CC[O-]
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc2nnc(N)n2n1
Temperature: 55 °C
Reaction time: 2 h
Yield: 108.9 %

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.001a, 616 mg) was dissolved in absolute ethanol (40 ml) and admixed with portions of solid sodium ethoxide (990 mg). After stirring at 55° C. for 2 h, water was added and the aqueous phase was extracted three times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated. 709 mg of crude product of the desired compound were obtained in sufficient purity.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH:19]=3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCN(c5ncc(Cl)cn5)CC4)oc3cn2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine and 2,5-dichloropyrimidine following a procedure analogous to that described for Example 23. LC (method 1): tR=1.07 min; Mass spectrum (ESI+): m/z=474/476 (Cl) [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:22]=[C:17]2[C:16]([C:30](=[O:46])[C:31]2[C:36]([F:37])=[CH:35][CH:34]=[C:33]([NH:38][S:39]([CH2:42][CH2:43][CH3:44])(=[O:41])=[O:40])[C:32]=2[F:45])=[CH:15]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[ClH:29].[NH2:8][CH2:9][C:10]([O:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH:22]=[C:17]2[C:16]([C:30](=[O:46])[C:31]2[C:36]([F:37])=[CH:35][CH:34]=[C:33]([NH:38][S:39]([CH2:42][CH2:43][CH3:44])(=[O:40])=[O:41])[C:32]=2[F:45])=[CH:15]1)=[O:11]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)CNC(=O)OC(C)(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)CN)c3ncc(-c4ccc(Cl)cc4)cc23)c1F

Procedure:
The title compound was prepared according to the procedure as described in Example 17 Step 3 using (5-(4-chlorophenyl)-3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl 2-((tert-butoxycarbonyl)amino)acetate (46 mg, 0.07 mmol) and a saturated solution of HCl in EtOAc (2 mL). The title compound was obtained as a white solid (36 mg, 83.7%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:37]=[N+:38]=[N-:39])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]4[NH:39][N:38]=[N:37][N:24]=4)=[N:19][CH:20]=[N:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:25]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2cncnc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2cncnc2-c2nnn[nH]2)cc1

Procedure:
A solution of methyl 2-butyl-1-[p-(4-cyanopyrimidin-5-yl)benzyl]benzimidazole-7-carboxylate (0.18 g, 0.4 mmol) and trimethyltin azide (0.27 g, 1.3 mmol) in toluene (5 ml) was heated under reflux for 28 hours. After removal of the solvent by evaporation, the residue was purified by column chromatography on silica gel. Recrystallization from ethyl acetate-isopropyl ether afforded colorless powders (40 mg, 20%), m.p. 215°-220° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:28])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1
Agent: [K+]
Solvent: CI
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 161, step 1, 5-[(R)-3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=410.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CNCC[C@H]1O
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of (3S,4R)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxypiperidine-1-carboxylate (1.94 g, 5.54 mmol) in ethanol (48 mL) was added to a hydrogenation flask containing 10% Pd/C (0.059 g, 0.554 mmol) that had been evacuated and back-filled with N2 (×3). The flask was again evacuated and then back-filled with H2 (×3). Enough H2 to allow complete reaction was then introduced to a burette and the system closed and the flask allowed to stir under a H2 atmosphere overnight. The reaction mixture was filtered through Celite and washed with EtOH (2×20 mL) and ethyl acetate (2×20 mL). The combined filtrate was concentrated in vacuo to afford the product as a cream oily solid—tert-butyl((3S,4R)-4-hydroxypiperidin-3-yl)carbamate (1.13 g, 5.22 mmol, 94% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH3:25])[C:16]=1[CH3:32])=[O:14].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5](=[O:10])[C:4]=1[CH2:11][NH:12][C:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27]2)[CH3:25])[C:16]=1[CH3:32])=[O:14]
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCCNC2)c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCCN(S(C)(=O)=O)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.8 %

Procedure:
To a solution of N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-3-yl)ethyl)-1H-indole-3-carboxamide (20 mg, 45.81 mol) in dichloromethane (3 mL) was added triethylamine (9.27 mg, 91.63 μmol) and methanesulfonyl chloride (7.87 mg, 68.72 μmol). The mixture was stirred at room temperature for 12 hours. The mixture was evaporated and purified by preparative-HPLC (Instrument: Gilson GX281 Column: Phenomenex Gemini C18 250*21.2 mm Mobile phase A: water with 0.01 mol/1NH4HCO3; Mobile phase B: MeCN Column temperature: 30° C. Gradient: 23-53% B 10 min) to afford the title compound (7 mg, yield: 29.69%). LRMS (M+H+) m/z: calc'd 515.22. found 515.2. 1H NMR (400 MHz, METHANOL-d4) δ 0.94-1.12 (m, 2 H) 1.39 (br. S., 2 H) 1.57-1.70 (m, 4 H) 2.33 (s, 3 H) 2.63 (s, 3 H) 2.83 (d, J=9.54 Hz, 2 H) 2.88 (s, 3 H) 3.48 (br. S., 1 H) 3.79-3.87 (m, 1 H) 3.95 (s, 3 H) 4.38 (br. S., 1 H) 4.54 (s, 2 H) 6.28 (s, 1 H) 7.07-7.17 (m, 2 H) 7.58 (d, J=8.03 Hz, 1 H) 7.72 (d, J=7.53 Hz, 1 H).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O>C(O)C>[CH:3]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:14]=3[CH2:13][CH2:12][C:11]=2[N:4]=[CH:1][CH:2]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: C#CCN
Solvent: CCO
Product: c1ccc2c(c1)CCc1ncccc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Propargylamine (5 mL) is added to a flask charged with a stir bar, 2-tetralone (10.00 g), NaAuCl4*2H2O (0.65 g), and ethanol (50 mL) (caution: a very exothermic reaction may evolve afterwards→keep an ice bath at hand). The resulting mixture is stirred at room temperature for 15 min and then at reflux temperature for 1 h. After cooling the mixture to room temperature, the solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 60:40) to afford the title compound as an oil. Yield: 6.78 g (56% of theory); LC (method 1): tR=1.81 min; Mass spectrum (ESI+): m/z=182 [M+H]+. Alternatively, the reaction may be conducted in a microwave oven heating with microwave irradiation to 100° C. for 10 min.
Reaction SMILES: Br/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH2:9]([NH:16][CH2:17][CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:9]([N:16]1[CH2:17][CH2:18][N:19]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][CH:2]1[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)/C=C(/C)Br
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In toluene (250 ml), N,N′-dibenzylethylenediamine (12 ml) and triethylamine (12 ml) were dissolved, followed by the dropwise addition of methyl 3-bromocrotonate (7.0 ml) under ice cooling. The resulting mixture was stirred at room temperature for 24 hours. After the addition of triethylamine (2.0 ml), the resulting mixture was stirred at room temperature for 71 hours. The insoluble matter was filtered off and the filtrate was distilled under reduced pressure. The residue was added with 10% hydrochloric acid (300 ml) and crystals so precipitated were removed by filtration. Ethyl acetate was added to the filtrate. Potassium carbonate was added to the water layer so separated to make it alkaline. Ethyl acetate was added to the resulting mixture. The organic layer so separated was washed with saturated saline and dried over anhydrous potassium carbonate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=4:1), whereby the title compound (1.07 g, 62%) was obtained.
Reaction SMILES: [CH:1]1[C:17]2[C:16](C(O)=O)=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH:1]1[C:17]2[CH:16]=[C:15]3[C:7](=[C:8]4[C:13](=[N:14]3)[CH:12]=[CH:11][CH:10]=[CH:9]4)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1c2nc3ccccc3c-2[nH]c2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1ccc2[nH]c3c4ccccc4nc-3cc2c1
Temperature: 30 °C
Yield: 91.2 %

Procedure:
A mixture of quindoline-11-carboxylic acid prepared in Example 1 (29.2 g, 0.111 mol) and diphenylether (300 mL) was refluxed for 6 hours, cooled to 30° C. and diluted with petroleum ether (250 mL). The precipitate which formed was filtered and washed with petroleum ether thoroughly, yielding 22.1 g (90.9%) of the title compound. A portion of this material was further purified by LPLC (ethyl acetate-hexane 1:3), mp 249°-251° C. [lit 251°-252° C. (Degutis, Y. A.; Ezyarskaite, A. B. Khim. Geterotsik. Soedin. 1986, 1375)]; 1H NMR (DMSO-d6) δ 11.43 (s, 1H, NH), 8.36 (d, J=7.8, 1H), 8.29 (s, 1H), 8.19 (d, J=8.4, 1H), 8.10 (d, J=8.2, 1H), 7.67-7.53 (m, 4H), 7.27 (t, J=7.4, 1H); 13C NMR (DMSO-d6) δ 145.72, 144.03, 143.39, 132.44, 129.68, 128.68, 127.48, 126.71, 126.01, 124.84, 121.34, 120.97, 119.33, 112.99, 111.49; MS (EI, m/z) 218.1 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:7]1(=[O:25])=[O:24].[CH3:26][NH2:27].Cl>>[F:16][C:13]1[CH:14]=[CH:15][C:9]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:7](=[O:25])(=[O:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH3:26])[CH2:11][C:10]=2[CH:12]=1
Reactant: O=S1(=O)N(CCCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Reactant: CN
Agent: Cl
Product: CNCCCCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Yield: 81 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.25 mmol) was reacted to methylamine and then treated with HCl to provide 4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine (0.085 g, 81%) as a white solid:
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:18](=[O:19])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:8]=3[O:9][C:10](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][NH2:21]>C(Cl)(Cl)Cl>[NH2:20][N:21]1[C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18](=[O:19])[C:7]=2[C:6]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[C:10]1=[O:9]
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Reactant: NN
Solvent: ClC(Cl)Cl
Product: Nn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Benz[d]indeno[1,2-b]pyran-5,11-dione (4d) (0.150 g, 0.604 mmol) was treated with hydrazine (0.255 g, 7.964 mmol) in CHCl3 (50 mL) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was allowed to cool to room temperature, diluted with CHCl3 (150 mL), and washed with sat NaHCO3 (2×50 mL). The solution was dried over sodium sulfate and concentrated to provide a red-orange solid (0.120 g, 76%): mp 272-274° C. IR (film) 3448, 3305, 1686, 1663, 1610, 1507, 1312, 762 cm−1; 1H NMR (CDCl3) δ 8.54 (d, J=7.8 Hz, 1H), 8.51 (d, J=7.2 Hz, 1H), 8.24 (d, J=7.4 Hz, 1H), 7.85 (m, 1H), 7.60-7.45 (m, 4H), 6.19 (s, 2H); EIMS m/z (rel intensity) 262 (M+, 100). Anal. (C16H10N2O2.0.25H2O) C, H, N.