Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1]/[C:2](=[CH:8]/[CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])/[C:3](OCC)=[O:4].[H-].C([Al+]CC(C)C)C(C)C.Cl>CCCCCC>[F:1][C:2](=[CH:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14])[CH:3]=[O:4]
Reactant: CCOC(=O)/C(F)=C\CCO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCC=C(F)C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
6.91 Grams of ethyl (E)-2-fluoro-5-(tertbutyldimethylsilyloxy)-2-pentenoate was dissolved in 50 ml of hexane under a nitrogen atmosphere. The resulting solution was cooled to -78° C. in a dry ice-acetone bath, and 26 ml of diisobutylaluminum hydride (as 1.0 M hexane solution) was added dropwise. After additon, the solution was stirred at -78° C. for 1 hour. The reaction solution was poured into cooled 5% hydrochloric acid, and after separating the hexane layer, the aqueous layer was extracted twice with ether. The ether extracts were combined with the above hexane layer, and this mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure to obtain 5.50 g of 2-fluoro-5-(tert-butyldimethylsilyloxy)-2-pentenal [E form/Z form (11:1) mixture by NMR determination].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)CCC>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)[CH:3]=2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Reactant: OC1CCNCC1
Solvent: CCCCO
Product: CS(=O)(=O)c1ccc(Nc2cc(N3CCC(O)CC3)nc(-c3ccccc3)n2)cc1

Procedure:
The (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.18 g, 0.48 mmol) was treated with 4-hydroxy piperidine (0.097 g, 0.97 mmol) in n-butanol at refluxing temperature for 12 hour to give the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11]2[C:6](=[CH:7][C:8]([N+:23]([O-])=O)=[C:9]([NH:12][C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:10]=2)[NH:5][C:4](=[O:26])[CH2:3]1>[Pd].C(O)C>[CH3:1][C:2]1([CH3:27])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[N:23][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:26])[CH2:3]1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)CC3(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)CC(=O)N4)cc1

Procedure:
6.8 g. (18.4 mmole) 4,4-dimethyl-6-(4-methoxybenzoylamino)-7-nitro-1,2,3,4-tetrahydroquinolin-2-one were hydrogenated in 200 ml. ethanol in the presence of 0.6 g. 10% palladium on charcoal. After filtering off of the catalyst, the filtrate was mixed with 15 ml. concentrated hydrochloric acid and boiled under reflux for 20 hours. The evaporation residue was mixed with water and ammonia, extracted with methylene chloride/methanol (20:1 v/v), purified over silica gel (elution agent:methylene chloride/ammonia-saturated methanol; 20:1 v/v) and recrystallized from ethanol to give 3.5 g. (60% of theory) of the title compound; m.p. 235°-238° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[C:7]=1[OH:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>C1(C)C=CC=CC=1>[NH2:26]/[C:4](/[C:3]1[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=1[F:1])=[C:6]1\[C:7](=[O:15])[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[S:10]\1
Reactant: O=C(c1ccccc1F)c1sc2ccccc2c1O
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1F
Yield: 50 %

Procedure:
Prepared as in Example 1 from 2-(2-fluorobenzoyl)benzo[b]-thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia, but using a mixture of toluene and petroleum ether in a volume ratio of 2:1 in place of pure toluene, giving a yield of 50% of theory. Yellow crystals; m.p. 156°-158° C. (ethyl acetate/petroleum ether 1:1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O.S(Cl)(Cl)=O.[CH2:25]([NH2:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:25]([NH:43][C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)C=Cc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
Under a nitrogen atmosphere, 4-acetoxycinnamic acid (150 g) and N,N-dimethylformamide (5 ml) were suspended in chloroform (800 ml) and thereto was added dropwise thionyl chloride (104 g) over a period of about 30 minutes. After completion of the addition, the reaction mixture was reflexed with heating for 1 hour to prepare the corresponding acid chloride. The reaction mixture was cooled to room temperature and thereto was added dropwise a solution of octadecylamine (196 g) and triethylamine (81 g) in chloroform (50 ml) over a period of about 30 minutes, followed by refluxing with heating for 3 hours. The reaction mixture was cooled to room temperature to precipitate a white crystal, which was filtered off under reduced pressure and dried to obtain N-octadecyl-p-acetoxycinnamamide (258 g). Yield 78%. This was suspended in 1,4-dioxane (1200 ml) and thereto was added aqueous KOH solution 50%; 127 g) and the reaction was allowed to proceed at 40°-45° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature to precipitate a white crystal, which was filtered off under reduced pressure. This crystal was washed with distilled water and recrystallized from methanol to obtain the desired product (211 g). Yield 90%; m.p. 114° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[C:33]([O:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])=[CH:34][C:35]2[N:39]=[N:38][N:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[C:36]=2[CH:46]=1.[F-].[Cs+]>C(O)CCC.O.C(OCC)(=O)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl>[F:55][C:49]1[CH:50]=[C:51]([F:54])[CH:52]=[CH:53][C:48]=1[O:47][C:33]1[C:32]([C:6]2[C:5]3[CH:17]=[CH:18][N:19]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)(=[O:21])=[O:22])[C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)=[CH:46][C:36]2[N:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[N:38]=[N:39][C:35]=2[CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: Fc1ccc(Oc2cc3nnn(C4CCCCO4)c3cc2Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc5c(cc4Oc4ccc(F)cc4F)nnn5C4CCCCO4)cn(C)c(=O)c32)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
A solution of 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.0720 g, 0.168 mmol), 6-bromo-5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-benzotriazole (0.069 g, 0.17 mmol), 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) (1.8 mg, 0.00252 mmol), and cesium fluoride (0.0894 g, 0.589 mmol) in 1-butanol (0.765 mL) and water (0.18 mL) was degassed with nitrogen for 5 min and stirred at 110° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 80% EtOAc/hexanes) gave the desired product (77 mg, 72%) as a yellow solid that was not entirely pure. This material was used without further purification. LCMS calculated for C32H28F2N5O5S (M+H)+: m/z=632.2. found: 632.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([F:11])[CH:4]=2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)c(F)c2)CC1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
4-Bromo-3-fluorobenzoic acid (4.38 g) was dissolve in tetrahydrofuran (50 mL), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.6 g), 1-hydroxybenzotriazole 1hydrate (3.24 g) and piperazine-1-carboxylic acid tert-butyl ester (4.47 g) were added, and the mixture was stirred at room temperature. The reaction mixture was poured into water under cooling, 4N aqueous sodium hydroxide solution and ethyl acetate were added and the mixture was extracted with ethyl acetate. The organic layer was washed with 4N aqueous sodium hydroxide solution and saturated brine, then washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (7.01 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:26]([NH2:29])(=[O:28])=[O:27])=[CH:16][CH:15]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:30])[CH:3]=1.CC1(C)[SiH2][SiH]=[N:35][C:34](C)(C)C1(C)C.[Na].BrC#N.CC(O)=O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[S:26]([NH:29][C:34]#[N:35])(=[O:27])=[O:28])=[CH:18][CH:19]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:30])[CH:3]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Agent: N#CBr
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2S(=O)(=O)NC#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5,7-dimethyl-2-ethyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (122 mg, 0.29 mmol) in THF (1.5 mL) at 0° C. was added sodium hexamethyldisilazine (0.35 mL of a 1M solution in THF). After 10 min, a solution of BrCN (37 mg, 0.35 mmol) in THF (1 ml) was added dropwise via a double tipped needle. The reaction was warmed to r.t. and stirred for 3 h at which time 0.3 mL of HOAc was added. Extraction with CH2Cl2 (5×30 mL) from H2O (30 mL), evaporation of the organic extracts and purification (SiO2, 80:19:1 CH2Cl2 /CH3OH/NH4OH) gave 5,7-dimethyl-2-ethyl-3-[2'-(N-cyanoaminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine as a glass.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[CH2:12][CH2:13][CH2:14]C[N:7]3[C:8]=2[C:3]=1[C:4](=[O:16])[CH2:5][CH2:6]3.C[O:18][C:19]1C=CC=C2[C:20]=1[CH:21]=[CH:22]C(N)=C2>>[OH:18][C:19]1[C:11]2[C:2](=[C:3]3[C:8]4=[C:9]([CH2:12][CH2:13][CH2:14][N:7]4[CH2:6][CH2:5][C:4]3=[O:16])[CH:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc2cc(N)ccc12
Reactant: O=C1CCN2CCCCc3ccc(O)c1c32
Product: O=C1CCN2CCCc3cc4c(O)cccc4c1c32

Procedure:
The title compound was synthesized in a similar manner as 11-hydroxy-2,3,5,6,7,8-hexahydro-1H-azepino[3,2,1-ij]quinolone starting from 5-methoxy-2-aminonaphthalene: 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 7.55 (s, 1H); 7.08-7.00 (m, 2H), 6.48 (dd, 1H), 3.14 (q, 4H), 2.86 (q, 2H), 2.02-1.86 (m, 4H); MS expected 240 (C16H18NO, M+1), found 240.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(4-chloro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:8]#[C:9]Br.[OH-].[Na+].[Na+].[OH-]>>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]#[N:8])[CH2:4][CH2:3]1
Reactant: N#CBr
Reactant: CC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CC1CCN(C#N)CC1

Procedure:
In the manner given in Example 1, 4-methylpiperidine is treated with cyanogen bromide and aqueous sodium sodium hydroxide to give 4-methyl-1-piperidinecarbonitrile.
Reaction SMILES: [C:1]([S:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].FC(F)(F)S(O)(=O)=O>CSC.C(Cl)Cl>[C:1]([S:4][CH2:5][C:6]1([C:16]([NH:18][CH2:19][CH:20]([C:22]([OH:24])=[O:23])[OH:21])=[O:17])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCC1(C(=O)NCC(O)C(=O)OCc2ccccc2)CCc2ccccc2C1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)SCC1(C(=O)NCC(O)C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester (882 mg, 2.00 mmol) in dimethylsulfide (2 mL) and add trifluoromethane sulfonic acid (0.2 mL). Stir at ambient temperature under an atmosphere of argon for 1 hour. Dilute to a volume of 50 mL with methylene chloride and extract with brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the crude product. Purify the residue by column chromatography (acetic acid:ethyl acetate:hexane) to give the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[N:9]=[CH:8]2)=[O:4].CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[F:32][C:26]1[CH:27]=[C:28]([I:31])[CH:29]=[CH:30][C:25]=1[NH:24][C:6]1[C:5]([C:3]([OH:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Nc1ccc(I)cc1F
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)ccc32)cc1
Yield: 91.7 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid methyl ester (0.51 g, 0.91 mmol) in toluene (5 mL) was added bis(tributyltin) oxide (0.92 mL, 1.8 mmol) and the reaction mixture heated at reflux for 48 hours. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (Si—PPC, gradient 0-10% methanol in DCM) to yield the title compound as a light brown solid (0.46 g, 92%). LCMS (Method B): RT=4.27 min, [M+H]+=552.
Reaction SMILES: [CH:1]1([C:7]2[N:8]([C:12]3[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=3[N+:26]([O-:28])=[O:27])[C:15]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH3:22])=[O:16])[CH:9]=[CH:10][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:31]I>CN(C)C(=O)C.O>[CH:1]1([C:7]2[N:8]([C:12]3[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=3[N+:26]([O-:28])=[O:27])[C:15]([N:17]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[CH3:31])=[O:16])[CH:9]=[CH:10][N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCCNC(=O)c1ccc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOCCN(C)C(=O)c1ccc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)c1
Reaction time: 1.8 h

Procedure:
To the solution of 3-(2-cyclohexyl-1H-imidazol-1-yl)-N-(2-ethoxyethyl)-4-nitrobenzamide as synthesized in above Production Example 48, 3.86 g in N,N-dimethylacetamide 32 mL, sodium hydride (formed by washing 60% sodium hydride, oiliness 600 mg with hexane) was added under cooling with ice. Then methyl iodide 1.55 mL was added and the ice bath was removed. After 1.8 hours' stirring, sodium hydride (formed by washing 60% sodium hydride, oiliness 200 mg with hexane) was added, followed by 5 hours' stirring. The reaction liquid was poured in water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Distilling the solvent off, 3.35 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([N:5]([CH2:13][C:14](=[O:35])[CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2][CH:3]=[CH2:4].[CH2:36]=O>C1COCC1>[CH2:1]([N:5]([CH2:13][C:14](=[O:35])[CH:15]=[CH2:36])[C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH2:2][CH:3]=[CH2:4]
Reactant: C=O
Reactant: C=CCCN(CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CCCN(CC(=O)C=C)C(=O)OC(C)(C)C
Temperature: 18 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
To a mixture of tert-butyl N-but-3-enyl-N-[2-oxo-3-(triphenyl-phosphanylidene)propyl]carbamate (5.80 g, 11.90 mmol, 1.00 Eq) in THF (30 mL), was added HCHO (96.58 g, 1.19 mol, 100.00 Eq) in one portion at 18° C. The mixture was stirred at 18° C. for 15 hr. TLC showed the reaction was completed. The mixture was extracted with PE (100 mL*3). The combined organic phase was washed with saturated brine (200 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=50/1, 40/1) to afford tert-butyl N-but-3-enyl-N-(2-oxobut-3-enyl)carbamate (1.40 g, 5.85 mmol, 49.16% yield) as yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH:20]([CH3:22])[CH3:21])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2](=[O:1])[CH:20]([CH3:21])[CH3:22])=[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=1
Reactant: COc1ccc(CC(O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc(CC(=O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a solution of tert-butyl [2-(2-hydroxy-3-methylbutyl)-5-methoxyphenyl]-carbamate (100 mg) in dichloromethane (1.5 mL) was added Dess-Martin periodinane (164 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtrated through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (94 mg). 1H-NMR (CDCl3) δ ppm: 1.13 (6H, d, J=7.0 Hz), 1.52 (9H, s), 2.72-2.86 (1H, m), 3.66 (2H, s), 3.80 (3H, s), 6.59 (1H, dd, J=2.6, 8.5 Hz), 7.02 (1H, d, J=8.5 Hz), 7.47 (1H, br s), 7.60-7.90 (1H, br).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[N:20][C:19]=12>CO>[N:15]1[CH:16]=[CH:17][N:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[N:20][C:19]=12
Reactant: O=Cc1ccn2ccnc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: OCc1ccn2ccnc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
Sodium triacetoxyborohydride (21.5 g, 102 mmol) was added portionwise over 20 min to a stirred solution of imidazo[1,2-α]pyrimidine-7-carbaldehyde (5.00 g, 34.0 mmol) in methanol (100 ml) and the solution left to stir at ambient temperature for 18 h. The solvent was evaporated, the residue redissolved in methanol (150 ml) and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with dichloromethane (containing 1% conc. ammonia) on a gradient of methanol (1-10%) gave imidazo[1,2-α]pyrimidin-7-ylmethanol (5.06 g, 99%) as a white solid: δH (360 MHz, DMSO) 4.57 (2H, d, J 6), 5.62 (1H, t, J 6), 7.13 (1H, d, J 7), 7.64 (1H, d, J 1), 7.86 (1H, d, J 1), 8.94 (1H, d, J 7).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1.[CH2:44](OC(OCC)C1C=CC(C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)=NC=1)C>>[CH2:4]([O:3][CH:2]([O:1][CH2:6][CH3:5])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1)[CH3:44]
Reactant: CCOC(OCC)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Product: CCOC(OCC)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Yield: 31 %

Procedure:
Following the procedure described above for the synthesis of compound 32 (Scheme 9) but substituting compound 31 for compound 52, title compound 53 was obtained in 31% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.46 (s, 1H), 11.82 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.37 (s, 1H), 8.29 (dd, J=8.2, 0.8 Hz, 1H), 8.02 (d, J=11.9 Hz, 1H), 7.91 (dd, J=8.1, 1.7 Hz, 1H), 7.53-7.52 (m, 2H), 7.37 (dd, J=8.8, 5.7 Hz, 2H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (dd, J=5.4, 0.9 Hz, 1H), 5.63 (s, 1H), 3.82 (s, 2H), 3.64-3.50 (m, 4H), 1.17 (t, J=7.0 Hz, 6H). MS (m/z): 635.1 (M+H).