Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:36]([O:35][C:33]([N:27]1[CH2:32][CH2:31][N:30]([CH2:21][C:12]2[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[N:15]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[CH:11]=2)[CH2:29][CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)cc1F
Yield: 94.3 %

Procedure:
Following the procedure of Example 1(10), 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 94.3%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(O)C.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCC(=O)O)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-5-methyl-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 52 was suspended in a mixed solution of ethanol (10 ml) and methylene chloride (10 ml), and IN aqueous solution of sodium hydroxide (1 ml) was added to the suspension. The mixture was stirred at room temperature for 90 minutes, and the solvent was evaporated under reduced pressure. To the residue was added water and 1N hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration to obtain the title compound (170 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].[Cl:20][CH2:21][C:22](Cl)=O>C(O)(=O)C>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:22]([CH2:21][Cl:20])=[N:1]2
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Yield: 27.7 %

Procedure:
Prepared according to Procedure B with 1l (2.6 g, 9.41 mmol) and chloroacetyl chloride (2.2 mL, 28.2 mmol) in acetic acid (40 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 874 mg of a pale yellow solid (28%). 1H NMR (CDCl3) δ: 7.55-7.74 (m, 2H); 7.47-7.54 (m, 2H); 7.34 (dd, J=1.7, 7.8 Hz, 1H); 7.13 (dt, J=1.2, 7.7 Hz, 1H); 7.08 (dd, J=1.0, 8.4 Hz, 1H); 4.29 (d, J=12 Hz, 1H); 4.11 (d, J=12 Hz, 1H); 3.80 (s, 3H). MS (ES): m/z 335.0 (M+).
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]2)=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[O:20]=[S:21]1(=[O:30])[CH2:26][CH2:25][N:24]([C:27](Cl)=[O:28])[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:27]([N:24]2[CH2:25][CH2:26][S:21](=[O:30])(=[O:20])[CH2:22][CH2:23]2)=[O:28])=[O:13])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C(Cl)N1CCS(=O)(=O)CC1
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide hydrochloride (150 mg; 0.521 mmol) in THF (6 mL) is added 1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl chloride (102.97 mg; 0.521 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.07 mmol). The reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is quenched with water and extracted with methylene chloride twice. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 413 [M+H+].
Reaction SMILES: N#N.COC1C=CC(C([NH:24][C:25]2[NH:26][C:27](=[O:65])[C:28]3[N:29]=[CH:30][N:31]([C@@H:34]4[CH2:37][C@H:36]([CH2:38]O)[C@H:35]4[CH2:40][O:41]C(C4C=CC=CC=4)(C4C=CC(OC)=CC=4)C4C=CC(OC)=CC=4)[C:32]=3[N:33]=2)(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[ClH:68].[CH3:69][N:70]([CH3:77])[CH2:71][CH2:72][CH2:73][C:74]([OH:76])=[O:75].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O.C(OCC)(=O)C.CN(C=O)C>[ClH:68].[CH3:69][N:70]([CH3:77])[CH2:71][CH2:72][CH2:73][C:74]([O:76][CH2:38][C@H:36]1[CH2:37][C@@H:34]([N:31]2[CH:30]=[N:29][C:28]3[C:27](=[O:65])[NH:26][C:25]([NH2:24])=[N:33][C:32]2=3)[C@@H:35]1[CH2:40][OH:41])=[O:75]
Reactant: CN(C)CCCC(=O)O
Reactant: COc1ccc(C(Nc2nc3c(ncn3[C@@H]3C[C@H](CO)[C@H]3COC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)c(=O)[nH]2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CN(C)CCCC(=O)OC[C@H]1C[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
Under a stream of argon gas, N2 -(4,4'-dimethoxytrityl)-9-[(1R,2R,3S)-2-(4,4'-dimethoxy-trityl)oxymethyl-3-hydroxymethyl-1-cyclobutyl]-guanine (360 mg, 0.41 mmole), 4-(dimethylamino)-butyric acid hydrochloride (138.7 mg, 0.83 mmole) and 4-(dimethyl-amino)-pyridine (10.1 mg, 0.08 mmole) are dissolved into DMF (4 ml), and then the DMF is distilled off under reduced pressure. The residue is dissolved into DMF (4 ml). Pyridine (0.17 ml, 2.07 mmoles) and dicyclohexyl-carbodiimide (DCC) (170.8 mg, 0.83 mmole) are added thereto, and the resulting mixture is stirred at room temperature overnight. After adding water (4 ml) to the reaction mixture and stirring the mixture for one hour, ethyl acetate and water are added and insoluble matter is filtered off. The filtrate is extracted with ethyl acetate. The extract layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Then, volatile substances are distilled off under reduced pressure. 80% acetic acid (30 ml) is added to the residue and stirred overnight. After distilling off the volatile substances from the reaction mixture under reduced pressure, water is added and the water is distilled off. Water is added to the residue and the resulting mixture is washed with ether, after which pH value is adjusted to 9. The solution thus obtained is purified by CM Sephadex column chromatography (water, 0.5M NaCl) and then de-salted by the use of a de-salting apparatus (Microacylizer G-1, mfd. by Asahi Kasei Kogyo) to obtain 9-[(1R,2R,3S)-3-(4-dimethylamino-butyryl)oxymethyl-2-hydroxymethyl-1-cyclobutyl]-guanine hydrochloride (52.0 mg, 30.3%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:11]2[C:6]([C:7]3([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)=[CH:5][CH:4]=1.O1CCOCC1.[ClH:36]>>[ClH:36].[F:29][C:2]([F:1])([F:28])[C:3]1[N:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]3([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(C(F)(F)F)ccc12
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Reaction time: 0.33 h

Procedure:
tert-Butyl 1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (30 mg, 0.074 mmol) was dissolved in hydrogen chloride in dioxane (700 μL of 4.0 M, 2.8 mmol). The reaction mixture was allowed to stand for 20 minutes. The solvent was evaporated to give 1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] hydrochloride was then used without further purification (25 mg, 99%). 1H NMR (400 MHz, DMSO) δ 9.23 (br s, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.40-7.19 (m, 3H), 7.05 (d, J=3.9 Hz, 1H), 6.38 (d, J=4.0 Hz, 1H), 3.42-3.04 (m, 4H), 2.37-2.00 (m, 4H). ESI-MS m/z calc. 308.3, found 309.5 (M+1)+; Retention time: 1.53 minutes (3 min run).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[N:8][CH:9]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1>[NH:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([O:3][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])=[O:2])=[CH:9][N:8]=2)=[N:11][N:12]=[N:13]1
Reactant: O=C(O)c1ccc(-c2nnn[nH]2)nc1
Reactant: CCCCCCCCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(-c2nnn[nH]2)nc1

Procedure:
A mixture of 1.65 g (8.6 mmol) of 5-carboxy-2-(5-tetrazolyl)-pyridine , 0.1 ml of concentrated sulfuric acid and 3.64 g (15 mmol) of 1-hexadecanol in 50 ml of toluene is refluxed for 48 h. The hot solution is filtered in order to eliminate the non-reacted starting material. The filtrate on cooling yields crystals of the title compound, m.p. 139°-140°.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]([N:18]=[N+:19]=[N-:20])[O:14][CH2:15][CH2:16][OH:17])[CH:6]=1)C.[OH-].[Na+]>C(O)C>[N:18]([CH:13]([O:14][CH2:15][CH2:16][OH:17])[CH2:12][O:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:21])=[O:3])=[N+:19]=[N-:20]
Reactant: CCOC(=O)c1cccc(OCC(N=[N+]=[N-])OCCO)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: [N-]=[N+]=NC(COc1cccc(C(=O)O)c1)OCCO
Reaction time: 3 h

Procedure:
3-[2-Azido-2-(2-hydroxy-ethoxy)-ethoxy]-benzoic acid ethyl ester (1.34 g, 4.55 mmol) was stirred with 4 M aqueous sodium hydroxide (11.4 ml, 45.5 mmol) and ethanol (11.4 ml) at room temperature. After 3 hrs, all the solvents were removed under reduced pressure and the residue was dissolved in 50 ml water. The solution was acidified with 1 N HCl to pH 2 and then extracted with DCM (3×50 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The title compound was obtained as a colourless solid (1.2 g, 98.7%). ES-MS, m/z 265.85 (M−1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH2:13][NH:14][C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].[Cl-].ClC=[N+](C)C.[C:24](=O)([O-])[O-:25].[K+].[K+]>ClCCCl>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([CH:24]=[O:25])[CH:9]=[C:8]1[CH2:13][NH:14][C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NCCn1c(C)ccc1CNC(C)=O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCCl
Product: CC(=O)NCCn1c(CNC(C)=O)cc(C=O)c1C
Reaction time: 1.5 h

Procedure:
4.9 g of N-((1-(2-acetylaminoethyl)-5-methyl-1H-pyrrol-2-yl)methyl)acetamide in 70 ml of 1,2-dichloroethane are added dropwise to 3.0 g (21 mmol) of chloromethylenedimethylammonium chloride in 30 ml of 1,2-dichloroethane at 10° C. The mixture is subsequently stirred for 90 min, hydrolysed using potassium carbonate solution and worked up as described in Example 1.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:20](=[O:21])[C:19]2[C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[CH:16]=4)[NH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[C:5]1=[O:6].C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[Br:25][CH2:2][CH2:3][N:4]1[C:20](=[O:21])[C:19]2[C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:22][CH3:23])[CH:16]=4)[NH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[C:5]1=[O:6]
Reactant: COc1ccc2[nH]c3ccc4c(c3c2c1)C(=O)N(CCO)C4=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3ccc4c(c3c2c1)C(=O)N(CCBr)C4=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
In 4.5 ml of N,N-dimethylformamide was dissolved 450 mg of N-(2-hydroxyethyl)-6-methoxycarbazole-3,4-dicarboximide. Thereto were added 1.06 g of carbon tetrabromide and 840 mg of triphenylphosphine. The mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of water and 50 ml of ethyl acetate. The mixture was stirred at room temperature for 10 minutes. The resulting insoluble material was removed by filtration. The organic layer was separated from the filtrate, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 230 mg (yield: 42%) of N-(2-bromoethyl)-6-methoxycarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[C:5]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][C:20](=[O:22])[CH3:21])[N:15]=[CH:14][NH:13]C2=O)(=[O:7])[CH3:6].C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:4][C:1]1[C:11]2[C:16](=[CH:17][C:18]([O:19][C:20](=[O:22])[CH3:21])=[C:9]([O:8][C:5](=[O:7])[CH3:6])[CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Oc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2ncnc(Cl)c2cc1OC(C)=O
Temperature: 27.5 °C

Procedure:
Into a 3.0 L four necked round bottomed flask, equipped with a mechanical stirrer, reflux condenser, pressure equalizing addition funnel and thermometer socket are charged chloroform (1000 ml), 6,7-diacetoxy-4(3H)-quinazolinone (50 g) obtained by the process described in step (ii) above and dimethylformamide (2 ml). Oxalyl chloride (50 g) was slowly added in about 20-30 minutes. The reaction mass was slowly heated to reflux temperature and maintained at reflux temperature for 6 hours. Reaction was found to be over by HPLC. Cooled the reaction mass to 25-30° C. and slowly quenched into saturated sodium bicarbonate solution at less than 10° C. Separated the organic layer and dried over anhydrous sodium sulfate. The dried organic layer thus obtained was directly used in the next step without any purification.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[CH2:7]([Si:11]([CH2:14][CH2:15][CH2:16][CH3:17])(Cl)[Cl:12])[CH2:8][CH2:9][CH3:10]>C1COCC1>[CH2:7]([Si:11]([CH2:14][CH2:15][CH2:16][CH3:17])([Cl:12])[CH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH2:8][CH2:9][CH3:10]
Reactant: c1cc[cH-]c1
Reactant: CCCC[Si](Cl)(Cl)CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Si](Cl)(CCCC)C1C=CC=C1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
THF in a volume of 100 ml was added to 100 ml (200 mmol) of a 2M THF solution of sodium cyclopentadienide. The mixture was cooled to −78° C., and 100 ml of THF was added thereto. Further, 21.3 g (100 mmol) of dibutyldichlorosilane was gradually added dropwise. The mixture was stirred at room temperature for 24 hours and was concentrated under reduced pressure, and unreacted materials were distilled away. The residue was used in the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]#[C:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:17]=3)[C:12]3[CH:27]=[C:28]([Cl:31])[CH:29]=[N:30][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][CH:17]=3)[C:12]3[CH:27]=[C:28]([Cl:31])[CH:29]=[N:30][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(C#Cc3ccccc3)cc2c2cc(Cl)cnc21
Agent: [Pd]
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1c2ccc(CCc3ccccc3)cc2c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A solution of 9-benzenesulfonyl-3-chloro-6-(2-phenylethynyl)-9H-pyrido[2,3-b]indole (200 mg, 0.45 mmol, 1 equiv.) in anhydrous ethanol (25 ml) was treated with 10% palladium on carbon (50 mg, 0.047 mmol, 0.1 equiv.) and then stirred at room temperature under an atmosphere of H2 overnight. The reaction mixture was filtered through celite and then concentrated under reduced pressure. The crude product (pale yellow solid) was purified over silica gel chromatography (eluant CH2Cl2/PE 7:3) to afford the product 61 as a white solid (183 mg, 0.41 mmol) in 91% yield. mp=158-162° C.; IR 3057, 3023, 2926, 1494, 1475, 1432, 1376, 1366, 1255, 1182, 1712, 1090, 977, 908, 713, 683 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.48 (d, 1H, J=2.3 Hz, H2), 8.36 (d, 1H, J==8.7 Hz, H8), 8.12 (m, 3H, H4+H7+CHP), 7.67 (s, 1H, H5), 7.56-7.52 (m, 1H, CHP+CHPh), 7.45-7.38 (m, 3H, 3CHP or CHPh), 7.32-7.18 (m, 5H, CHP+CHPh), 3.12-2.97 (m, 4H, 2CH2); 13C NMR (75 MHz, CDCl3) δ 149.2 (C), 145.4 (CH), 141.4 (C), 138.7 (C), 138.1 (C), 137.0 (C), 134.2 (CH), 130.0 (CH), 129.1 (2×CH), 128.6 (2×CH), 128.6 (2×CH), 128.9 (2×CH), 127.6 (CH), 127.5 (C), 126.3 (CH), 122.0 (C), 120.6 (CH), 120.0 (C), 115.1 (CH), 38.2 (CH2), 38.8 (CH2); MS (+ESI) [M+H+]=447.1
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2)=O.O.NN.[OH-].[K+]>C(O)COCCO>[NH:14]1[C:15]2[C:11](=[C:10]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: O=C(c1ccccc1O)c1cccc2[nH]ccc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Oc1ccccc1Cc1cccc2[nH]ccc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 22.74 g of the product of Step D of Example 3, 49.4 ml of hydrazine monohydrate, 96 ml of diethylene glycol and 38.4 ml of 38% caustic potassium hydroxide was stirred for 30 minutes at 140° C. and after the mixture was heated to 210° C., the water and hydrazine hydrate were distilled off. Stirring was continued for one hour at 210° C. and the mixture was allowed to return to ambient temperature and poured into 300 ml of a saturated aqueous solution of sodium chloride. Extraction took place with ethyl acetate and the extracts were evaporated to dryness under reduced pressure. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 20.55 g of the desired product melting at 139° C. which was used as is for the following step.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.CO.O.NN>ClCCl>[F:36][C:2]([F:1])([F:35])[O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 50 °C
Yield: 95.4 %

Procedure:
To 2-(3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propyl)isoindoline-1,3-dione (C59) (0.373 g, 0.758 mmol) in a 25 mL vial equipped with a stir bar, Vigreux column, and nitrogen was added methanol (7.58 mL) followed by hydrazine monohydrate (0.110 mL, 2.27 mmol). The reaction was heated to 50° C. until determined to be complete by LCMS. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The layers were separated and the aqueous layer was extracted with dichloromethane (2×). The organic layers were washed with sodium hydroxide (1 N, 4×), poured through a phase separator and concentrated. The resultant solid was dried in vacuo over 72 hours at 50° C. to provide the title compound as an off-white solid (0.262 g, 95%): 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.10-8.04 (m, 2H), 8.04-7.98 (m, 2H), 7.66-7.59 (m, 2H), 7.35 (d, J=8.1 Hz, 2H), 2.69-2.63 (m, 2H), 2.56 (t, J=6.9 Hz, 2H), 1.74-1.59 (m, 2H), (NH2 not observed); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 363 ([M+H]+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].[C:38](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH:11]([NH:13][C:14](=[O:29])[C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)([CH3:17])[CH3:16])[CH3:12])[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC(NC(=O)C(C)(C)Oc1ccc(C(F)(F)F)cn1)C(Cc1ccc(O)cc1)c1cc(F)cc(C#N)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOCC
Product: COc1ccc(CC(c2cc(F)cc(C#N)c2)C(C)NC(=O)C(C)(C)Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C

Procedure:
To a solution of N-[2-(3-cyano-5-fluorophenyl)-3-(4-hydroxyphenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide from Example 7, Step B (14 mg, 0.028 mmol) in 1.5 mL of dimethylformamide at 0° C. was added cesium carbonate (14 mg, 0.042 mmol) and methyl iodide (5 uL, 0.084 mmol), and the reaction was allowed to warm up to room temperature over 2 h. The resulting mixture was diluted with ether (20 mL), washed with water and brine and concentrated to dryness. The residue was purified by flash column chromatography eluting with 10 to 40% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.27 (d, 1H), 7.96 (s, 1H), 7.94 (d, 1H), 7.93 (d, 1H), 7.29 (m, 1H), 7.18 (br s, 1H), 7.13 (m, 1H), 7.03 (d, 1H), 6.45 (ABq, 4H), 4.24 (m, 1H), 3.67 (s, 3H), 3.03 (dd, 1H), 2.88 (m, 1H), 2.57 (dd, 1H), 1.75 (s, 3H), 1.73 (s, 3H), 0.82 (d, 3H). LC-MS: m/e 530 (M+H)+ (3.9 min).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].C(O)(=O)C.C(O)(C(F)(F)F)=O.[Br:25]Br>O>[Br:25][C:13]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[NH:11][C:10](=[O:12])[O:9][C:7](=[O:8])[C:6]=12
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1Br
Temperature: 5 °C

Procedure:
To a suspension of 5-methyl-isatoic anhydride (9.2 g, 0.052 mol) in a mixture of glacial acetic acid (60 mL) and TFA (30 mL), bromine (9.9 g, 0.062 mol) was added under stirring at 5° C. Reaction mixture warmed to room temperature and stirred˜5 hours. Poured in cold water and yellow ppt filtered and washed with water and dried. Yield: 12.09 g, 90%.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.