Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(OC(C)C)(C)C.N>C(OCC)(=O)C.CO>[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: C1CCN(CCC2CNCCO2)CC1
Agent: N
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2ccccc2N(C(=O)N2CCOC(CCN3CCCCC3)C2)c2ncccc21
Yield: 78 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-(1-piperidinyl)ethyl]morpholine in a yield of 78% of theory. Colourless crystals, m.p. 136°-138° C. (diisopropylether), Rf 0.46 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: ethyl acetate/methanol/conc. ammonia 100/30/3, v/v/v).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=2)=[N:25][N:24]=1.CC(O)(C)C>C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=5)=[N:25][N:24]=4)=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Reactant: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: Cc1csc(-c2nnc(Nc3ccc(Oc4ncccc4-c4ccnc(N)n4)cc3)c3ccccc23)c1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine and 1-chloro-4-(4-methyl-2-thienyl)phthalazine was added tBuOH. The resulting mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine as an off-white solid. MS m/z=504 [M+H]+. Calc'd for C28H21N7OS: 503.58.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[Cl:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>CN(C=O)C>[Cl-:1].[Cl:28][C:29]1[CH:30]=[N+:31]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:7][CH:8]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Reactant: Clc1cccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C[n+]2cccc(Cl)c2)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 24 h

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg), and to the mixture was added 3-chloropyridine (122 μl). The mixture was stirred at 70° C. for 24 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3-chloro-1-[4-(7-phenyl-3,4-dihydronaphthalene-2-carboxamido)benzyl]pyridinium chloride (Compound 23) (110 mg) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@@H:34]([CH2:35][OH:36])[CH:37]([CH3:39])[CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CC(C)[C@@H](N)CO
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](CO)C(C)C)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (R)-2-amino-3-methyl-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H38N6O5SF [(M+H)+] 553.2603, observed 553.2600.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].O.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:11][S:12]([O:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OB(O)c1cccc(O)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-hydroxyphenylboronic acid (10 g) stirred in pyridine (40 mL) at 0° C. was added methanesulfonyl chloride (8 mL). The reaction mixture was stirred for 1 h at room temperature and then water and ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with dilute HCl washed with brine, dried over magnesium sulfate. The resulting solid was recrystallizated from petroleum ether and ethyl acetate to give the sub-titled compound (12 g).
Reaction SMILES: Cl[CH:2]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[C:18](=[O:19])[N:17]([CH:20]([F:22])[F:21])[C:16]([CH3:23])=[N:15]2)[C:11]([Cl:24])=[CH:10][C:9]=1[Cl:25])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+]>CN(C)C=O>[Cl:25][C:9]1[CH:10]=[C:11]([Cl:24])[C:12]([N:14]2[C:18](=[O:19])[N:17]([CH:20]([F:21])[F:22])[C:16]([CH3:23])=[N:15]2)=[CH:13][C:8]=1[CH:7]=[CH:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To a stirred, cold (0° C.) solution of 4.16 g (0.0100 mole) of methyl 2-chloro-3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-l,2,4 -triazol-1-yl)phenyl]propionate in 15 mL of N,N-dimethylformamide was added portionwise 0.29 g (0.012 mole) of sodium hydride. After complete addition the reaction mixture was allowed to warm to room temperature and was stirred for 30 minutes. The reaction mixture was heated at 60° C. for six hours, then was stirred at room temperature for approximately 18 hours. The reaction mixture was poured into ice water, and the resultant aqueous mixture was extracted with four portions of diethyl ether. The extracts were combined and washed successively with water and an aqueous, saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to give a white foam. The foam was purified by column chromatography on silica gel, eluting with n-heptane:ethyl acetate (4:1), to give 1.63 g of methyl 3-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-l,2,4-triazol-1-yl)phenyl]-2-propenoate as a solid, m.p. 141°-151° C.
Reaction SMILES: I[C:2]([F:20])([F:19])[C:3]([F:18])([F:17])[C:4]([F:16])([F:15])[C:5]([F:14])([F:13])[C:6]([F:12])([F:11])[C:7]([F:10])([F:9])[F:8].C(=O)(O)[O-].[Na+:25].[S:26](S([O-])(=O)=O)([O-:29])(=O)=[O:27].[Na+].[Na+].O>C(#N)C>[C:2]([S:26]([O:29][Na:25])=[O:27])([C:3]([C:4]([C:5]([C:6]([C:7]([F:10])([F:9])[F:8])([F:12])[F:11])([F:14])[F:13])([F:16])[F:15])([F:18])[F:17])([F:20])[F:19]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: O=S(=O)([O-])S(=O)(=O)[O-]
Reactant: [Na+]
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Product: O=S(O[Na])C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
1-Iodoperfluorohexane (89.2 g, 0.2 mol) was added rapidly to a stirred mixture of 16.8 g (0.2 mol) of sodium bicarbonate, 418 g (0.24 mol) sodium dithionate, 60 mL of water and 60 mL of acetonitrile at room temperature. After 1.5 hr, the mixture was heated to 55° C. and maintained for 4 hr. The mixture was then concentrated on a rotary evaporator to remove the acetonitrile. Ethyl acetate (250 mL) was added and the mixture was faltered. The solid was dissolved in an additional 200 mL of ethyl acetate. The combined ethyl acetate solutions were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The solid residue was recrystallized three times from 350 mL of isopropanol to give in two crops 55 g of white solid. 19F NMR (CDCl3) -80.6 (3F), -121.6 (2F), -122.2 (2F), -122.4 (2F), -125.7 (2F), -130.7 (2F).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COC1CCCC1.O.CCO.O.COC1CCCC1>[NH2:35][C:34]1[CH:36]=[CH:37][C:31]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[CH:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COC1CCCC1
Solvent: CCO
Product: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3)nc(N3CCOC[C@@H]3C)c2C1
Temperature: 100 °C
Yield: 89.5 %

Procedure:
(S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) (1.0 g, 3.06 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (805 mg, 3.67 mmol), Pd(PPh3)2(Cl)2 (107 mg, 0.15 mmol) and Na2CO3 (487 mg, 4.59 mmol) were stirred in CPME/Water/EtOH (14/1/6 mL) under nitrogen for 5 mins, followed by heating at 100° C. overnight. The reaction mixture was then diluted with water and CPME, and precipitate collected by filtration to give 1.05 g of a brown solid. A portion of the brown solid was further purified by prep. HPLC to give 32.6 mg of an off-white solid.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1.Cl[C:21]1[C:22]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=N[CH:24]=[CH:25][N:26]=1.[CH3:40]N(C=O)C>CCOC(C)=O.O>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][CH:16]([O:19][C:21]2[C:22]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:31][CH2:32]3)=[CH:40][CH:24]=[CH:25][N:26]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Reactant: CN(C)C=O
Reactant: OC1CCN(c2ccc3ccccc3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 254 mg, 10.58 mmol) was added to a solution of 1-(quinolin-2-yl)piperidin-4-ol (see PREPARATION P1.1; 805 mg, 3.53 mmol) in DMF (16.8 ml) under an atmosphere of nitrogen and the mixture was stirred for 15 mins at RT. Tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (see PREPARATION P16.1; 1050 mg, 3.53 mmol) was next added, and the mixture was heated at 100° C. After the reaction was complete, the mixture was cooled to RT and diluted with EtOAc and water. The layers were separated and the aqueous was extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered and concentrated and used in the next step without further purification.
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][C:7](B3OCCNCCO3)=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Br[C:39]1[C:48]([O:49][CH:50]([F:52])[F:51])=[C:47]2[C:42]([C:43](=[O:61])[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:45][N:46]2[CH:53]2[CH2:55][CH2:54]2)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(Cl)Cl.C(OCC)(=O)C>[CH:53]1([N:46]2[C:47]3[C:42](=[CH:41][CH:40]=[C:39]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[C@@H:2]([CH3:1])[N:3]([C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:4]5)[C:48]=3[O:49][CH:50]([F:52])[F:51])[C:43](=[O:61])[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:45]2)[CH2:55][CH2:54]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(Br)ccc2c1=O
Reactant: C[C@@H]1c2ccc(B3OCCNCCO3)cc2CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]4C)ccc2c1=O
Yield: 89.5 %

Procedure:
In a mixed solvent of 2 ml of water and 5 ml of ethyl acetate is suspended 1.34 g of 2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocane and to this suspension are added 1.0 g of ethyl 7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.55 g of sodium carbonate and 0.05 g of bis(triphenylphosphine)palladium(II) chloride, after which the resulting mixture is heated under reflux for 3 hours in a nitrogen atmosphere. The reaction mixture is added to a mixed solvent of 10 ml of methylene chloride and 10 ml of water and the organic layer is separated. The organic layer obtained is washed with saturated saline and then dried over anhydrous magnesium sulfate, after which the solvent is removed from the layer by distillation under reduced pressure. The residue obtained is recrystallized from ethanol to obtain 1.55 g of ethyl 1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[CH2:8]([Cl:11])[CH:9]=[CH2:10]>>[Si:1]([Cl:11])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[Si:1]([CH2:10][CH2:9][CH2:8][Cl:11])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: CC[SiH](CC)CC
Reactant: C=CCCl
Product: CC[Si](CC)(CC)CCCCl
Product: CC[Si](Cl)(CC)CC
Temperature: 27 °C
Reaction time: 1 h
Yield: 15.5 %
Yield: 42 %

Procedure:
In a 100 ml apparatus, there were combined 11.6 g (0.1 mol) of Et3SiH, 7.7 g (0.1 mol of allyl chloride, and 0.05 ml Pt catalyst solution at 19° C. After stirring 1 hr, temperature had increased to 27° C., followed by heating at 70° C. for 17 hr. The incomplete reaction was vacuum distilled, yielding 8.9 g (42%) of Et3SiCl, and 3.0 g (15.5%) of Et3SiCH2CH2CH2Cl. The Et3SiCH2CH2C2Cl/Et3SiCl molar selectivity ratio was 0.37. This example shows that the unpromoted reaction between Et3SiH and CH2 =CHCH2Cl is very slow.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12)[NH2:5].FC1C=CC([NH:26][C:27]([C:29]2([C:32](O)=[O:33])[CH2:31][CH2:30]2)=[O:28])=CC=1.C1(C(O)=O)(C(O)=O)CC1.[F:44][C:45]1[CH:51]=[CH:50][C:48](N)=[CH:47][CH:46]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:5]([C:48]2[CH:50]=[CH:51][C:45]([F:44])=[CH:46][CH:47]=2)[C:32]([C:29]2([C:27]([NH2:26])=[O:28])[CH2:30][CH2:31]2)=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[CH:17][S:18][C:11]=12
Reactant: Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: O=C(O)C1(C(=O)O)CC1
Product: NC(=O)C1(C(=O)N(c2ccc(F)cc2)c2ccc(Oc3ccnc4ccsc34)c(F)c2)CC1
Yield: 25 %

Procedure:
Prepared from 3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 1, Step B; 130 mg, 0.50 mmol) and 1-((4-fluorophenyl)carbamoyl) -cyclopropanecarboxylic acid (123 mg, 0.550 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods described in WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) according to the procedure described for Example 10. The crude was purified by preparative TLC (10% MeOH/CH2Cl2). The product was obtained as a waxy solid (60 mg, 25%). 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.75 (m, 2H), 7.56 (d, J=5 Hz, 1H), 7.45 (m, 2H), 7.26 (m, 2H), 7.06 (m, 2H), 6.51 (d, J=5 Hz, 1H), 1.80 (m, 2H), 1.62 (m, 2H). LRMS (ESI pos) m/e 466 (M+1). HPLC: 97% purity (220 nm).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11](=[O:26])[C:12]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(NCC#CCO)C(O)(c1ccccc1)C1CCCCC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(NCC#CCCl)C(O)(c1ccccc1)C1CCCCC1

Procedure:
Thionyl chloride (4.8 ml) was added dropwise to a mixture of N-(4-hydroxy-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide (6.56 g) and N,N-dimethylformamide (5 drops) in dry chloroform (145 ml) at 0° C. and the reaction mixture was refluxed for 1 hour. The mixture was washed successively with water, 1N aqueous sodium hydroxide solution, and sodium chloride, aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (5:1) as an eluent to give N-(4-chloro-2-butynyl)-2-cyclohexyl-2-hydroxy-2-phenylacetamide as white powder (6.7 g).
Reaction SMILES: CN(OC)[C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH2:30].[O:31]1[CH2:35]C[CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[O:6][C:5](/[CH:3]=[CH:33]/[C:32]([O:31][CH3:35])=[O:30])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C)cc2)o1
Reactant: O
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(-c2ccc(C)cc2)o1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a solution of N-methyl-N-methoxy-5-(4-methylphenyl)furan-2-carboxamide (2.5 g) in tetrahydrofuran (20 ml) was added diisobutylaluminum hydride (1.01M toluene solution) (15 ml) at −78° C., and the mixture was stirred at −78° C. for 10 minutes and then at 0° C. for 15 minutes. To the reaction mixture was added 1N hydrochloric acid to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:5→1:4) to give crude product (1.49 g). A solution of the crude aldehyde (1.49 g) and methyl (triphenylphosphoranilidene)acetate (2.67 g) in toluene (30 ml) was refluxed under nitrogen atmosphere for 1 hour and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9→1:5) to give methyl (E)-3-[5-(4-methylphenyl)furan-2-yl]acrylate (1.63 g) as pale yellow crystals.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C@:10]2([CH2:19][C@H:18]2[C:20]2[CH:28]=[C:27]3[C:23]([CH:24]=[N:25][N:26]3CC3C=CC=CC=3)=[CH:22][CH:21]=2)[C:9]1=[O:36])C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+]>CS(C)=O>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([C@H:18]3[C@@:10]4([C:11]5[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=5)[NH:8][C:9]4=[O:36])[CH2:19]3)[CH:28]=2)[CH:24]=[N:25]1
Reactant: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cnn(Cc4ccccc4)c3c1)C(=O)N2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 100 mL flask charged with (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (469 mg, 1 mmol) was added dry THF (2 mL) and the resulting mixture was stirred at 0° C. before KOtBu (1 M in THF, 18 mL, 18 mmol) was added over 2 min. After addition, the resulting mixture was stirred for 15 min at 0° C. and DMSO (1.85 mL) was added. Oxygen was bubbled through for 1 h and reaction turned from homogeneous to heterogeneous. LC-MS showed good conversion at 50 min. It was quenched with sat. NH4Cl. The above reaction was repeated on a larger scale using (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (1.41 g, 3 mmol). After quenching with saturated NH4Cl, two reactions were combined, diluted with H2O and extracted with EtOAc (100 mL×2). Purification by Biotage Isolera (10-95% EtOAc in hexane) gave the title compound as a light solid (680 mg, 53%). 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.46 (s, 1H), 6.94 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.78 (s, 1H), 3.32 (t, overlapping with MeOH residue), 2.20-2.12 (m, 2H), 1.87 (s, 3H); MS ESI 290.1 [M+H]+, calcd for [C18H15N3O+H]+ 290.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([OH:20])=O)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:43]1([CH2:49][CH2:50][CH2:51][NH2:52])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>ClCCl.CC(=O)OCC.CO>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]([NH:52][CH2:51][CH2:50][CH2:49][N:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[O:20])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCN1CCCCC1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccccc1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=C(NCCCN1CCCCC1)c1ccc2c(c1)C(=O)N(Cc1ccccc1)C2
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 2-benzyl-3-oxoisoindoline-5-carboxylic acid (Chemical Formula 8) (100 mg, 0.374 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.144 g, 0.749 mmol), and 1-hydroxybenzotriazole (HOBT, 0.025 g, 0.187 mmol) were reacted at room temperature in distilled dichloromethane, with stirring, for 2 hours. After monitoring through TLC [CH2Cl2:MeOH=4:1], the temperature was decreased to −40° C. at which time 3-(piperidin-1-yl)propan-1-amine (80 μL, 0.562 mmol) was added before stirring for 3-4 hours. The reaction progress was monitored with TLC [Hex: EA=1:1]. When the reaction was completed, the reaction mixture was extracted with NaHCO3 and then with CH2Cl2. The organic layer thus obtained was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum and the concentrate was purified using column chromatography [CH2Cl2:MeOH=20:1] to afford 2-benzyl-3-oxo-N-(3-(piperidin-1-yl)propyl)isoindoline-5-carboxamide (Chemical Formula 1) in an amount of 96 mg (Yield 73%). This product was solidified with ethereal HCl to give a hydrochloride.