Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.[ClH:18].CCOC(C)=O>C(OCC)(=O)C>[ClH:18].[OH:1][CH:2]([CH3:17])[CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CC(O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(O)CC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 233 mg of tert-butyl 4-(2-hydroxy propyl)piperidine-1-carboxylate in 4 mL of ethyl acetate was added 3 mL of 4M HCl/EtOAc, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure to obtain 4-(2-hydroxypropyl)piperidine hydrochloride. To a solution of the 4-(2-hydroxypropyl)piperidine hydrochloride and 155 mg of indole-2-carboxylic acid in 5 mL of DMF were added 0.15 mL of triethylamine, 190 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 130 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then solidified using diisopropyl ether to obtain 49 mg of 1-[1-(1H-indol-2-ylcarbonyl)piperidin-4-yl]propan-2-ol as a white solid.
Reaction SMILES: CSC.B.[NH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[O:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[N:22]=4)[N:17]=[CH:16][C:15]=3[NH:14][C:13]2=O)[CH2:8][CH2:7]1.ClCCl.CO>O1CCCC1>[CH3:27][O:26][C:21]1[N:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]1[NH:14][CH2:13][CH:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([NH2:5])[CH2:7][CH2:8]3)[O:25][C:24]2=1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)C(=O)N3
Agent: B
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)CN3
Temperature: 0 °C

Procedure:
Borane dimethyl sulfide complex (2M solution in tetrahydrofuran, 12.5 mL, 25.0 mmol, 10.0 eq) is added at room temperature to a stirred solution of 3-(trans-4-amino-cyclohexyl)-6-methoxy-1H-4-oxa-1,5,9-triaza-phenanthren-2-one (821 mg, 2.50 mmol, 1.0 eq) in tetrahydrofuran (80 mL). The reaction mixture is heated to reflux for 3 hours, cooled down to 0° C. and cautiously quenched with methanol (10 mL) and then evaporated to give a residue that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 1:1, v/v) to afford trans-4-(6-methoxy-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexylamine as a yellow solid (340 mg, 45% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[N:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C@@H:11]([NH:20][C:21]2[N:26]=[C:25]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=3)[C:24]([N:42]3[CH2:47][CH2:46][CH:45]([C:48]([O:50]CC)=[O:49])[CH2:44][CH2:43]3)=[CH:23][N:22]=2)[CH2:10][C@H:9]1[CH2:53][CH3:54])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[N:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[C@@H:11]([NH:20][C:21]2[N:26]=[C:25]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:29]=3)[C:24]([N:42]3[CH2:43][CH2:44][CH:45]([C:48]([OH:50])=[O:49])[CH2:46][CH2:47]3)=[CH:23][N:22]=2)[CH2:10][C@H:9]1[CH2:53][CH3:54])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2cnc(N[C@H]3C[C@@H](CC)N(C(=O)OC(C)(C)C)c4ccc(OC)nc43)nc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](Nc2ncc(N3CCC(C(=O)O)CC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c2nc(OC)ccc2N1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(4-ethoxycarbonyl-piperidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid tert-butyl ester (120 mg) is dissolved in 1,4-dioxane (1 ml), and thereto is added 1M aqueous NaOH solution (1 ml). The mixture is stirred at 50° C. for 1 hour. After 10% aqueous citric acid solution is added to the reaction mixture, the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(4-carboxypiperidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid tert-butyl ester (77 mg). MS (m/z): 739 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[CH3:23][S:24]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)COc1cccc(CO)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)COc1cccc(COS(C)(=O)=O)c1
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of ethyl 2-(3-(hydroxymethyl)phenoxy)acetate (2.00 g) and triethylamine (1.44 g) in THF (10 mL) was added methanesulfonyl chloride (1.31 g) at 0° C., and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.80 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](OC4CCCCC4)=[CH:17][CH:18]=3)[C:13]([C:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH:32]=3)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(OC2C=C3C(=CC=2)NC=C3C2CCN(C)CC=2)CCCCC1.ClC1C=CC(S(Cl)(=O)=O)=CC=1>>[CH3:33][N:30]1[CH2:31][CH:32]=[C:27]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([S:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)(=[O:9])=[O:10])[CH:12]=2)[CH2:28][CH2:29]1
Reactant: CN1CC=C(c2cn(S(=O)(=O)c3ccc(Cl)cc3)c3ccc(OC4CCCCC4)cc23)CC1
Agent: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Agent: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1

Procedure:
1-(4-Chlorophenylsulfonyl)-5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)indole: (37.7 mg, 94%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.5 mg, 0.082 mmol) and 4-chlorophenylsulfonyl chloride (35.6 mg, 0.169 mmol); HRMS-FAB+ for C26H29N2O3SCl: calculated MH+ : 485.16656; found: 485.16480.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[C:27]([F:37])=[CH:28][C:29]([F:36])=[C:30]([S:32]([NH2:35])(=[O:33])=[O:34])[CH:31]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (68 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (85 mg, 65%). MS (ISN) 517.0 [(M−H)−]; mp 255–257° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]([Br:12])=[CH:10][S:9][CH:8]=1.[C:13](=[O:15])=[O:14]>CCOCC>[Br:12][C:11]1[C:7]([C:13]([OH:15])=[O:14])=[CH:8][S:9][CH:10]=1
Reactant: Brc1cscc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(O)c1cscc1Br
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
To 400 ml of dry ether, under nitrogen, cooled to -70° C., was added a solution of 256 ml of n-butyllithium (1.6 m in hexane). A solution of 96.8 g of 3,4-dibromothiophene in 600 ml of ether was added, dropwise over a 20 minute period, maintaining the reaction temperature between -78° C. and -60° C. After stirring for an additional 5 minutes, the solution was transferred via a double-tipped needle, under nitrogen pressure, to an already prepared solution of 80 g of crushed dry ice in 400 ml of ether. The temperature was maintained at below -50° C. during this addition. The resulting white mixture was stirred for 5 minutes, quenched with 800 ml of water, and the layers separated. The etheral layer was washed with 500 ml of saturated sodium bicarbonate solution. The aqueous layers were combined and acidified with concentrated hydrochloric acid to yield a white solid which was filtered off and recrystallized from water/ethanol (5:2) to give 73 g of the title compound as needles; m.p. 157°-158° C.
Reaction SMILES: [CH2:1]=[C:2]=[CH:3][CH3:4].C=CC=C.C#CCC.CC#CC.[CH:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH3:1][CH2:2][C:3]#[C:4][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC=O
Reactant: C=C=CC
Agent: C#CCC
Agent: C=CC=C
Agent: CC#CC
Solvent: C1CCOC1
Product: CCC#CC(O)CCCCC

Procedure:
Following the procedure of Example 1, but with a pressure equalizing dropping funnel in place of the gas addition tube, 5.2 g. of lithium metal powder and 125 ml. of tetrahydrofuran are added to the flask. 65 g. of ammonia gas is condensed into the slurry with stirring forming a liquid-copper-gold colored lithium ammonia adduct. 190 g. of a mixture containing about 18% 1,2-butadiene, 21% 1,3-butadiene, 4% 1-butyne, 3.3% 2-butyne and about 25% isomeric butenes dissolved in 800 ml. tetrahydrofuran was added over a 70 minute period with stirring while maintaining the temperature at about 50°C. to 60°C. The mixture was refluxed to drive off excess gases and cooled. An aliquot of the product was reacted with 1-hexanal producing 3-decyn-5-ol which by gas chromotograph analysis, establishes a yield of butynyllithium in excess of 90%, based on lithium.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])=[N:9][C:10]2[N:11]([C:17](=[O:32])[NH:18][C:19]3[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]([C:30]#[N:31])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.[CH3:38][NH2:39]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:30]([C:22]1[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][NH:39][CH3:38])=[C:8]([CH:33]([O:34][CH3:35])[O:36][CH3:37])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:32])=[N:20][CH:21]=1)#[N:31]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCc1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of (8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 170, 363 mg, 0.679 mmol) in THF (8 ml) was added methylamine 2 M in THF (5 ml, 10.00 mmol) at room temperature and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO3 and DCM. Phases were separated and the water phase was extracted with DCM (3×), organic phases were combined and dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with a gradient of MeOH (including 3% NH3, 10-20%) in DCM. Fractions containing the product were combined and evaporated to yield the title compound as a colorless solid. (UPLC-MS 3) tR 0.70 min, ESI-MS 470.2 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 13.60 (s, 1H), 8.27 (s, 1H), 7.74 (s, 1H), 7.53 (s, 1H), 6.92 (t, 1H), 5.50 (s, 1H), 3.96-3.91 (m, 2H), 3.73 (s, 2H), 3.53 (t, J=5.8 Hz, 2H), 3.42-3.34 (m, 8H), 3.30 (s, 3H), 2.84 (t, 2H), 2.28 (s, 3H), 1.95-1.87 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1 g, 5.84 mmol), 4-hydroxypiperidine (0.65 g, 6.42 mmol) and 4 Å molecular sieves (10 g) in DCE (50 mL) The reaction mixture was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (2.48 g, 11.68 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc:cyclohexane, gradient 0:100 to 100:0) to give 3-(4-Hydroxypiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.34 g, 23%). 1H NMR (CDCl3, 400 MHz) δ 3.92 (t, J=7.8 Hz, 2H); 3.87-3.72 (m, 3H);(m, 1H); 2.68-2.63 (m, 2H); 2.09-2.03 (m, 2H); 1.96-1.91 (m, 2H); 1.69-1.55 (m, 2H); 1.43 (s, 9H).
Reaction SMILES: N[C:2]1[CH:6]=[CH:5][NH:4]N=1.CC(O[C:12]([C:14]1[CH:19](C(C)C)[N:18]2[N:23]=[CH:24][CH:25]=[C:17]2[NH:16][C:15]=1[CH3:26])=[O:13])(C)C>>[CH3:26][C:15]1[NH:16][C:17]2[N:18]([N:23]=[CH:24][CH:25]=2)[CH2:19][C:14]=1[C:12]([N:16]1[CH2:17][CH2:25][N:4]([C:5]2[CH:6]=[CH:2][CH:19]=[CH:14][CH:12]=2)[CH2:26][CH2:15]1)=[O:13]
Reactant: CC1=C(C(=O)OC(C)(C)C)C(C(C)C)n2nccc2N1
Reactant: Nc1cc[nH]n1
Product: CC1=C(C(=O)N2CCN(c3ccccc3)CC2)Cn2nccc2N1

Procedure:
Condensation of compound 3 and compound 4 as described in Example 18, Method 2 Step C provided the title compound. Reverse Phase LC/MS: YMC S5 ODS 4.6×50 mm Ballistic column, UV detection at 220λ, 4 min. gradient 0-100% Solvent B/A (Solvent A: 10% MeOH/H2O with 0.1% TFA, Solvent B: 90% MeOH/H2O with 0.1% TFA), 4 mL/min. Rt=1.96 min, (87% pure). (M+H: 323).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]2[N:22]=[C:21]([C@H:23]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:24][C:25]([O:27][C:28](C)(C)C)=[O:26])[O:20][N:19]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(Cl)OC(Cl)=O>C(Cl)Cl>[NH:14]1[CH2:17][CH:16]([C:18]2[N:22]=[C:21]([C@H:23]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)[CH2:24][C:25]([O:27][CH3:28])=[O:26])[O:20][N:19]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CN(C(c3ccccc3)c3ccccc3)C2)no1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: COC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CNC2)no1
Yield: 73.3 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(1-benzhydryl-3-azetidinyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 36) (1.99 g, 3.66 mmol) in DCM (15 ml) was treated with ACE-Cl (530 μl, 4.90 mmol) and heated at reflux for 4 hours. The solvent was removed under reduced pressure. The residue was dissolved in MeOH (15 ml) and heated at reflux for 1.5 hours. The solvent was removed under reduced pressure. The oil was dissolved in EtOAc (150 ml) and washed with sat. NaHCO3 solution (50 ml) and brine (40 ml). The aqueous extracts were combined and extracted with EtOAc. All of the organic extracts were combined, dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (900 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[C:17](I)=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:15][C:16]1[C:17]([C:14]#[C:13][CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])/[C:19]/2=[CH:26]\[C:27]1[NH:28][CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: C#CCNS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCNS(=O)(=O)c3ccc(C)cc3)c21

Procedure:
Using Method C above, 4-Methyl-N-(prop-2-ynyl)-benzenesulfonamide (130 mg, 0.62 mmol) (Example 119A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (Z)-N-[3-[5-Fluoro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-2,3-dihydro-1H-indol-4-yl]-prop-2-ynyl]-4-methyl-benzenesulfonamide was obtained after HPLC purification with 40% EtOAc in hexanes and precipitation out of THF with excess of hexanes. (Yield 42 mg, 44%).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([Cl:13])([Cl:12])[Cl:11])=[N:8][CH:9]=1)[CH3:3].[CH3:14][S-:15].[Na+]>C(O)C>[CH3:14][S:15][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([Cl:13])([Cl:12])[Cl:11])=[N:8][CH:9]=1)[CH3:3]
Reactant: C[S-]
Reactant: CC(Br)c1ccc(C(Cl)(Cl)Cl)nc1
Agent: [Na+]
Solvent: CCO
Product: CSC(C)c1ccc(C(Cl)(Cl)Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(1-bromoethyl)-2-(trichloromethyl)pyridine (A) (0.95 g, 3.14 mmol) in ethanol (15 mL) was treated with sodium thiomethoxide (0.44 g, 6.29 mmol) portionwise at 0° C. The mixture was stirred at room temperature overnight. The solvent ethanol was then removed under a reduced pressure and the residue was re-taken into CH2Cl2 and brine. The two phases were separated and the organic layer was dried over anhydrous Na2SO4, filtered, concentrated. The residue was purified on silica gel using 5% EtOAc in hexane to give 0.57 g of the partially pure 5-[1-(methylthio)ethyl]-2-(trichloromethyl)pyridine (B) in 67% crude yield. GC-MS: mass calcd for C9H10Cl3NS [M]+ 269. Found 269.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]1[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: Cc1cnc(CN)cn1
Product: Cc1cnc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cn1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (150 mg, 0.41 mmol) and 2-(aminomethyl)-5-methyl-pyrazine (60 mg, 0.49 mmol). The title compound was obtained as a solid (40 mg, 23% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.48 (1H, m), 8.98 (2H, s), 8.48 (1H, s), 8.47 (2H, m), 4.50 (2H, m), 2.50 (3H, s). MS m/z: 454.00, 456.04 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[N+:17]([O-])=O)[C:10](=[O:20])[NH:9][N:8]=2)=[CH:4][C:3]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]1)=[O:24]>[Pd].C(O)C>[NH2:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:7]([CH2:6][C:5]1[CH:21]=[CH:22][C:2]([F:1])=[C:3]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)=[O:24])[CH:4]=1)=[N:8][NH:9][C:10]2=[O:20]
Reactant: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc([N+](=O)[O-])c34)ccc2F)CC1
Agent: [Pd]
Solvent: CCO
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cccc(N)c34)ccc2F)CC1
Reaction time: 22 h
Yield: 29.8 %

Procedure:
4-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzyl)-5-nitrophthalazin-1 (2H)-one (45) (40 mg, 0.09 mmol) was added to 5% palladium on carbon (4 mg, 0.04 mmol) in ethanol (7 ml) at 25° C. under air. The resulting mixture was hydrogenated at 25° C. for 22 hours. The catalyst was filtered and washed with ethanol and the solvent evaporated to a pale brown gum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a beige solid (11 mg, 29.5% yield); 1H NMR (400.132 MHz, DMSO) δ 1.66-1.81 (2H, m), 1.86-1.96 (2H, m), 3.10-3.19 (1H, m), 3.36 (3H, s), 3.44-3.50 (2H, m), 3.55-3.64 (1H, m), 3.91-3.99 (1H, m), 4.08 (2H, s), 4.44 (2H, s), 6.99 (1H, d), 7.05-7.10 (1H, m), 7.23-7.28 (2H, m), 7.50-7.54 (1H, m), 7.94 (1H, d), 9.95 (1H, s); m/z (LC-MS, ESI+), RT=1.50 (M+H 411.3).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:21][CH2:20][CH2:19][C:18]3[CH:17]=[C:16]([C:22]4[N:23]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=5[F:34])[N:24]=[CH:25][N:26]=4)[S:15][C:14]=3[C:13]=2[N:35]=1)(C)(C)C.[ClH:37].O1CCOCC1>>[F:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[N:23]1[C:22]([C:16]2[S:15][C:14]3[C:13]4[N:35]=[C:9]([NH:8][CH2:7][C:6]([OH:36])=[O:5])[CH:10]=[CH:11][C:12]=4[O:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)=[N:26][CH:25]=[N:24]1.[ClH:37]
Reactant: CC(C)(C)OC(=O)CNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-acetic acid tert-butyl ester (900 mg, 1.76 mmol) was dissolved in dioxane-HCl (20 mL), and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was filtered to gather the solid. The resulting solid was washed by DCM (10 mL) to give 449 as HCl salt (500 mg, yield: 57%). 1H NMR (DMSO-d6, 400 MHz): δ8.27 (s, 1H), 7.82-7.90 (m, 1H), 7.63-7.69 (m, 1H), 7.61-7.62 (m, 2H), 7.35-7.40 (m, 2H), 7.21 (s, 1H), 6.95 (s, 2H), 6.52 (d, J=8.8 Hz, 1H), 4.15 (t, J=4.0 Hz, 2H), 3.88 (s, 2H), 3.05 (t, J=4.8 Hz, 2H). LC-MS (ESI): m/z=456 [M+H]+