Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[C:15]([C:17]([C:23]#[N:24])=[C:18]([NH:21][CH3:22])SC)#[N:16]>C(#N)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:18]([NH:21][CH3:22])=[C:17]([C:23]#[N:24])[C:15]#[N:16])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CNC(SC)=C(C#N)C#N
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Solvent: CC#N
Product: CNC(NCCCCc1csc(NC(=N)N)n1)=C(C#N)C#N

Procedure:
A mixture of 2-guanidino-4-(4-aminobutyl)thiazole (0.43 g.) and 1,1-dicyano-2-methylamino-2-methylthioethylene (0.3 g.) in acetonitrile (10 ml.) was heated under reflux for 16 hours. The mixture was then evaporated to dryness and the resulting gum purified by chromatography on a silica column using chloroform/methanol/ammonia (s.g. 0.880) 80:20:0.5 v/v/v as developing solvent to give 1-[4-(2-guanidinothiazol-4-yl)butylamino]-1-methylamino-2,2-dicyanoethylene.
Reaction SMILES: O.[NH2:2][NH2:3].Cl.Cl.NN.[N:8]#[C:9][NH2:10].[C:11](=[O:14])([OH:13])[O-:12].[Na+]>O>[C:11](=[O:12])([OH:14])[OH:13].[NH2:2][NH:3][C:9]([NH2:10])=[NH:8]
Reactant: O=C([O-])O
Reactant: NN
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N=C(N)NN
Product: O=C(O)O
Temperature: 25 °C
Yield: 96 %

Procedure:
Hydrazine hydrate (64% hydrazine, 20 lbs, 0.4-mole) was charged to a 30-gal glass-lined reactor and hydrochloric acid (32.1%, 45.4 lbs, 0.4 lb-mole) was added to it with stirring and cooling over 30 min. The resulting hydrazine hydrochloride solution was heated to 80° C. and cyanamide (50%, 36 lbs, 0.43 lb-mole) was metered in over ~30 min in 5-lb increments while maintaining the reaction temperature at ~85° C. Reaction is exothermic; introduction of an initial 7-lb charge of H2NCN caused a temperature excursion from 80° to 103° C. during the first minute. Thereafter, with full reactor cooling, the temperature was maintained at 80°-85° C. range during remainder of addition. The mixture was stirred at 85° C. for 2 hrs, then cooled to 25° C. and the pH measured, which showed a value of 7.6. A slurry of sodium bicarbonate (35 lbs, 0.42 lb-mole) in 65 lbs of water was added all at once and the reaction was stirred overnight. The white solid product was isolated by centrifugation, washed with water (4 gal), then returned to the reactor and resuspended with 150 lbs fresh water. A final centrifugation gave 82 lbs of wet-cake which was dried in a vacuum oven at ~35° C. and 29 in Hg. Assay of the dried material showed 99% AGB, for an overall yield of 96% based on hydrazine charged.
Reaction SMILES: C1(COC2C=CC=CC=2C(O)=O)C=CC=CC=1.C(Cl)(=O)OCC.N[C@@H:25]1[CH2:30][CH2:29][N:28]([CH:31](C)[CH2:32][C:33](C2C=CC=CC=2)(C2C=CC=CC=2)[C:34]([N:36](C)C)=[O:35])[CH2:27][C@H:26]1O>ClC(Cl)Cl.C(N(CC)CC)C>[N:28]1([CH2:31][CH2:32][CH2:33][C:34]([NH2:36])=[O:35])[CH2:29][CH2:30][CH2:25][CH2:26][CH2:27]1
Reactant: CC(CC(C(=O)N(C)C)(c1ccccc1)c1ccccc1)N1CC[C@@H](N)[C@H](O)C1
Agent: CCOC(=O)Cl
Agent: O=C(O)c1ccccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NC(=O)CCCN1CCCCC1
Reaction time: 8 h

Procedure:
To a stirred and cooled (ice bath) solution of 4 parts of 2-(phenylmethoxy)benzoic acid in 90 parts of trichloromethane were added first 1.47 parts of N,N-diethylethanamine and then 1.6 parts of ethyl carbonochloridate at <5° C. After stirring for 1 hour in an ice bath, the thus obtained mixture was added dropwise to a cooled solution of 5.94 parts of trans-4-amino-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-1-piperidinebutanamide in 90 parts of trichloromethane at a temperature below 5° C. Upon completion, stirring was continued overnight at room temperature. The organic layer was washed with water, a sodium carbonate solution in water and water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was C solidified in 2,2'-oxybispropane. The product was filtered off and dried in vacuo at 60° C. yielding 3.7 parts (40.7%) of trans-3-hydroxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[2(piperidinebutanamide: mp 149.0° C. (compound 29).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].N12CC3CC(CC(C3)C1)C2.O.[C:27]([O-])([O-])=[O:28].[K+].[K+]>C(O)(C(F)(F)F)=O>[C:10]1([C:2]([C:4]2[CH:9]=[CH:8][C:7]([CH:27]=[O:28])=[CH:6][CH:5]=2)([CH3:1])[CH3:3])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(c1ccccc1)c1ccccc1
Agent: C1C2CC3CC1CN(C2)C3
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
A suspension of propane-2,2-diyldibenzene (3.93 g, 20 mmol) and 1-aza-tricyclo[3.3.1.1*3,7*]decane (2.80 g, 20 mmol) in TFA (35 mL) was heated at 100° C. for 16 h. The reaction mixture was allowed to cool to RT, poured onto cold water and made alkaline (pH=9) with solid K2CO3. The aqueous solution was extracted with Et2O (3×250 mL) and the separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, petroleum ether:EtOAc 95:5) affording the title compound (3.47 g, 15.46 mmol).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH3:19][CH:20]([S-:22])[CH3:21].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:19][CH:20]([S:22][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1)[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
tert-Butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (Intermediate 239, 0.320 g, 1.15 mmol) and sodium 2-propanethiolate (0.147 g, 1.50 mmol) were combined in DMF (3 mL) and stirred at room temperature for 18 h. The mixture was then diluted with EtOAc (30 mL) and washed with water (3×10 mL). The organic layer was dried over sodium sulfate and concentrated to yield a yellow oil. This was purified by FCC, eluting with a gradient of 0-20% EtOAc in heptane to afford the title compound as a colourless oil (0.179 g, 60%). 1H NMR (500 MHZ, CDCl3) δ ppm 3.88 (2H, br s), 2.94 (1H, m), 2.86 (2H, m), 2.77 (1H, m), 1.83 (2H, d), 1.42 (2H, m), 1.38 (9H, s) and 1.20 (6H, d).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.O.[OH-].[Na+].Cl[C:34]([O:36][CH3:37])=[O:35]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH2:15][NH:16][C:34]([O:36][CH3:37])=[O:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccc(F)cc2F)CC1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)NCC(c1ccc(F)cc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To 4-[2-Amino-1-(2,4-difluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (209) (0.38 g, 1.13 mmol) in a 1:1 mixture of THF/H2O (30 mL) was added NaOH (0.05 g, 1.24 mmol) and methyl chloroformate (0.11 g, 1.13 mmol ). The reaction was allowed to stir at room temperature for 2 h. The reaction mixture was then diluted with EtOAc (200 mL) and washed with H2O (100 mL) and brine (100 mL). The organic phase was concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 50% hexanes/50% EtOAc) yielding 0.23 g (50%) pure product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12](=O)([O-])[O-].[K+].[K+].S([O:23][CH3:24])(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:12])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-Bromo-2-hydroxybenzoic acid (25 g) and 40 g of potassium carbonate were suspended in 300 mL of acetone. Dimethyl sulfate (28 mL) was added to the suspension, and the mixture was stirred for 19 hours under reflux with heating. The reaction mixture was cooled to room temperature, whereafter the insolubles were separated by filtration, and washed with ethyl acetate. The filtrate and the washings were combined, and acetone and ethyl acetate were distilled off under reduced pressure. The resulting residue was dissolved in 300 mL of ethyl acetate. Water (300 mL) was added to the solution, and the organic layer was separated; followed by extracting the aqueous layer with 200 mL of ethyl acetate. After the respective organic layers were combined, the combined organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was separated by filtration, and then washed with ethyl acetate. The filtrate and the washings were combined, and ethyl acetate was distilled off under reduced pressure to obtain 30 g of methyl 5-bromo-2-methoxybenzoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[C:5]2[CH3:17].[Cu][C:19]#[N:20]>>[CH3:17][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:19]#[N:20])[CH:3]=2)[NH:7][C:6]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#C[Cu]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Br)cc12
Product: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Temperature: 200 °C
Reaction time: 8 h

Procedure:
5-Bromo-3-methyl-2-pyridin-3-yl-1H-indole (5.0 g, 16.7 mmol) and copper (I) cyanide (1.9 g, 20.1 mmol) are placed in a round bottom flask which is flushed with N2. N-Methylpyrrolidinone (40 mL) is added via syringe. The resulting mixture is heated to 200° C. under N2 with vigorous stirring overnight. The mixture is cooled to room temperature and dichloromethane (200 mL) is added. The mixture is filtered through a pad of celite. The filtrate is washed with 10% aqueous ammonia in saturated aqueous ammonium chloride. The aqueous phase is extracted with dichloromethane. The combined organic phase is dried over sodium sulfate and concentrated. The residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:0) to give 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 7.45-7.60 (m, 3H), 8.06-8.11 (m, 1H), 8.15 (s, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H), 8.91 (d, J=1.5 Hz, 1H), 11.94 (br. s., 1H). HRMS (ESI) m/z 234.1031 [(M+H)+ Calcd for C15H11N3, 234.1031].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:47][CH2:46]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 60 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (57 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (83 mg, 0.108 mmol, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.35 (s, 1H), 8.44 (s, 1H), 8.19 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.52, 2.11 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.33-7.44 (m, 3H), 7.27 (d, J=8.61 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.93 (t, J=6.87 Hz, 1H), 6.67 (d, J=2.38 Hz, 1H), 6.51 (d, J=5.31 Hz, 1H), 6.48 (dd, J=8.79, 2.56 Hz, 1H), 3.97 (s, 3H), 3.79 (s, 3H), 3.30-3.35 (m, 2H), 3.11-3.20 (m, 4H), 3.03 (s, 3H), 2.74 (t, J=6.78 Hz, 2H), 2.52-2.62 (m, 4H). MS (ESI): 769 [M+H]+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(S([C:18]([F:21])([F:20])[F:19])(=O)=O)C=CC=CC=1>CN(C=O)C>[F:21][C:18]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])([F:19])[F:20]
Reactant: O=S(=O)(c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)C(F)(F)F
Temperature: -30 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Into a dry 250 mL Schlenk flask under an argon atmosphere, was added 5.14 g Mg turnings (214 mmol) and 32.3 g (214 mmol) t-butyldimethylsilyl chloride in 150 mL DMF at −30° C. Subsequently, 15.0 g (71.4 mmol) of 1 in 10 mL DMF was added slowly via a syringe. The reaction mixture was stirred at room temperature at −30° C. for 1 h, and then at room temperature for another 2 h until all the starting material was consumed (19F NMR showed that the conversion was 75%). The reaction mixture was washed with ice water, followed by extraction with pentane (30 mL×4 ). Combined pentane phase was further washed carefully with cold 98% sulfuric acid (20 mL×4) to remove most of the siloxane and silanol. Then the pentane phase was washed with cold NaHCO3 aqueous solution three times until pH paper indicated neutral pH. The pentane phase was dried over MgSO4 and solvent evaporated to give a crude product that was fractionally distilled to give 7.46 g colorless liquid 16 (95° C./410 Torr), which turned to a transparent crystalline solid at room temperature (m.p. 52˜54° C., sublimes), yield 57%. 1H NMR (500 MHz, CDCl3): δ0.20 (s, 6H); 0.99 (s, 9H). 13C NMR (125 MHz, CDCl3): δ−8.8; 16.0; 26.0; 132.0 (q, 1JC-F=323.8 Hz, CF3). 19F NMR (470 MHz, CDCl3): δ−61.8. 29Si NMR (99 MHz, CDCl3): δ8.4 (q, 1JSi-F=32.8 Hz). GC-MS (m/z): 184 (M+), 127 (M+-tBu), 115 (M+-CF3), 99 (M+-CF3—CH3), 57 (tBu+). High-resolution GC-MS (EI): m/z calculated for C7H15F3Si (M+) 184.0895, found 184.0943.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:17][CH:12]([N:13]([CH3:16])[CH:14]2[CH3:15])[CH2:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1.[ClH:18].[C:19]([Cl:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[OH2:1].[ClH:27].[ClH:18].[C:19]([O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:17][CH:12]([N:13]([CH3:16])[CH:14]2[CH3:15])[CH2:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.[C:19]([O:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:17][CH:12]([N:13]([CH3:16])[CH:14]2[CH3:15])[CH2:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1.[ClH:27].[ClH:27]
Reactant: CC1N(C)C2CCCC1(c1cccc(O)c1)C2
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC1N(C)C2CCCC1(c1cccc(OC(=O)c3cccnc3)c1)C2
Product: O
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a solution of 0.231 g of 1-(3-hydroxyphenyl)-6,7-dimethyl-6-azabicyclo[3,2,1]octane in 4 ml of pyridine is added 0.376 g of nicotinoyl chloride hydrochloride under icecooling. The solution is stirred at room temperature overnight. Then, the solution is concentrated under reduced pressure. The resudue thus obtained is washed with ether, and then recrystallized from a mixture of ethanol, acetone and ether. 0.17 g of 1-(3-nicotinoyloxyphenyl)-6,7-dimethyl-6-azabicyclo[3,2,1]octane dihydrochloride hemihydrate is obtained. M.p. 210° - 218°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1cccc(C(F)(F)F)c1
Yield: 64.1 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (163 mg, 0.50 mmol), 3-(trifluoromethyl)benzoic acid (950 mg, 5.00 mmol), 1-hydroxybenzotriazole (676 mg, 5.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (959 mg, 5.00 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (160 mg, 64%) was obtained as a white powder.
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23].CN(C)C=[O:27]>>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][O:27][C:7]1[CH:8]=[CH:3][CH:4]=[CH:5][C:6]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(/C=C/c2ccccc2)cc1
Reactant: ClCCCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: ClCCCCOc1ccccc1/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a suspension of sodium hydride (60%, 1.5 g, 38 mmol) in 200 ml dimethylformamide was added p-hydroxystilbene (5 g, 25 mmol), portionwise. The mixture was stirred at room temperature for 2 hours and 1-bromo-4-chlorobutane (4.4 mL, 38 mmol) was added. The mixture was then stirred at room temperature overnight. The reaction was quenched with methanol (10 mL) and filtered through Celite®. The filtrate was taken up in ether (250 mL), washed thrice with water (150 mL) and dried over sodium sulfate. The solution was concentrated to give 8.2 g (75%) of (E)-4-chlorobutoxystilbene as an amber oil. 1H NMR (CDCl3): δ7.62-6.81 (m,11H), 4.02 (t,2H), 3.63 (t,2H), 1.99 (m,4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1>>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=13)=[O:20])[CH2:25]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: COc1ccc(-c2nc3c(C(=O)O)cccc3o2)cc1
Agent: Cl
Product: COc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)cc1
Yield: 60 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-4-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-4-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 60% yield as a white solid: mp 103-105° C.; 1H NMR (500 MHz, CDCl3) δ 9.07 (m, 1H), 8.19 (m, 3H), 7.66 (dd, J=8.0, 1.1 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 7.07 (m, 2H), 4.60 (m, 1H), 3.92 (s, 3H), 3.11 (m, 2H), 2.66 (m, 2H), 2.54 (s, 3H), 2.13 (m, 1H), 2.03 (m, 2H), 1.53 (m, 3H), 1.17 (m, 2H); MS (ESI) m/z 406 [M+H]+
Reaction SMILES: [CH:1]([OH:7])(O)[CH2:2][CH2:3][CH2:4][CH3:5].C[Sn](Cl)(Cl)C.[C:13]([O-:16])([O-])=[O:14].[K+].[K+].C(Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:13]([O:16][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])(=[O:14])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCC(O)O
Reactant: O=C(Cl)c1ccccc1
Agent: C[Sn](C)(Cl)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCCCCCO)c1ccccc1

Procedure:
To a solution of pentanediol (1 mmol) in THF (5 ml) was added a catalytic amount of dimethyltin dichloride (0.01 mmol), solid K2CO3 (2.0 mmol) and benzoyl chloride (1.2 mmol), at room temperature. After stirring the mixture at room temperature until the diol disappeared (checked by TLC), the mixture was poured onto water and the organic portion was extracted with DCM. After evaporation of the solvent, a residue was obtained and purified by flash chromatography using a mixture of DCM/MeOH as eluent.
Reaction SMILES: [CH:1](=[C:8]([CH2:13][O:14]C(=O)C)[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH:1](=[C:8]([CH2:13][OH:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(=Cc1ccccc1)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(=Cc1ccccc1)CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
Methyl 2-benzylidene-3-acetoxypropionate [formula (IV), R1=Ph, R2=Me, R3=acetyl group, 143.9 g] obtained in Example 2 was dissolved in 400 ml of methanol, and an aqueous solution of 96.0 g (97%, 2.40 mols) of sodium hydroxide in 800 ml of water was added thereto. The resulting mixture was then stirred at room temperature for 90 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and methanol was distilled off. Subsequently, the residue was neutralized with the addition of 100 ml of water and 250 ml of 36% hydrochloric acid, and extracted with 600 ml of ethyl acetate. The resulting organic layer was washed with 300 ml of a saturated aqueous solution of sodium chloride, and insoluble matters were separated by filtration. The resulting solution was concentrated under reduced pressure. Toluene was added to the resulting residue in four divided portions in an amount of 250 ml each. The mixture was concentrated under reduced pressure, and acetic acid was removed to obtain 107.8 g of a crude product of the above title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[C:9](=[O:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH2:34]Br>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([C:9]2[O:13][CH2:33][CH2:34][C:10]=2[C:11]#[N:12])[CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: BrCCBr
Reactant: CCC(C(=O)CC#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C1=C(C#N)CCO1)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-1-cyano-2-oxopentan-3-yl)-1H-indol-4-yl)methanesulfonamide (50 mg, 0.116 mmol, enantiomer A), as described in Example 28 step A, in DMF (2 mL) was added NaH (9 mg, 0348 mmol, 60% in oil) at 0° C. After stirring for 30 min, 1,2-dibromoethane (22 mg, 0.116 mmol) was added to the mixture at 0° C. The resulting mixture was stirred at 0° C. for another 1 h, and then quenched with water (15 mL), extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (5/1 to 3/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=456.1[M+H]+.