Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:12][CH2:13][OH:14])[C:8]2[C:4](=[CH:5][N:6]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:7]=2)[CH:3]=1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:15][CH2:16][C:17]2([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:12][CH2:13][O:14][S:53]([CH3:52])(=[O:55])=[O:54])[C:8]2[C:4](=[CH:5][N:6]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:43])[CH3:44])[N:7]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CCO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COC(CCOS(C)(=O)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 110.5 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-3-hydroxypropoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (56 mg, 0.086 mmol) and TRIETHYLAMINE (0.036 ml, 0.259 mmol) in DCM (1.5 ml) at 0 C was added METHANESULFONYL CHLORIDE (0.013 ml, 0.173 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was cooled to 0 C and quenched by addition of sat'd sodium bicarbonate. The reaction was diluted with ether and the layers separated. The ethereal was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 69 mg title compound (quantitative yield). LC/MS (HPLC method 1): tR=4.42 min, 726.2(MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1ccnc2c1C(=O)CC(c1ccncc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccncc1)C2
Yield: 93.6 %

Procedure:
A mixture of 4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.1 g), aminoguanidine hydrochloride (0.049 g), concentrated hydrochloric acid (0.15 ml), water (0.15 ml) and ethanol (10 ml) was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol-water to give 5-guanidinoimino-4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 76) (0.13 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: CC1(c2cc(F)ccc2O)CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenol (23.5 g, 113 mmol), TEA (31 mL, 226 mmol) and DMAP (700 mg, 5.7 mmol) in CH2Cl2 (250 mL) was added methyl chloroformate dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured onto crushed ice and extracted with CH2Cl2 (100 mL×3). The organic layer was washed with brine, dried over MgSO4, evaporated under vacuum. The crude product was purified by chromatography on silica gel diluted with (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as red brown oil (43.9 g, 72.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=3.2, 11.2 Hz, 1H), 7.05-7.02 (m, 1H), 6.93-6.88 (m, 1H), 3.91 (s, 3H), 2.02-1.96 (m, 2H), 1.66-1.36 (m, 8H), 1.23 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=O.Cl.[NH2:25][OH:26].N1C=CC=CC=1.Cl>C(O)C>[CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C@H:3]1[CH2:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][CH:10]2[CH:22]=[N:25][OH:26]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(C=NO)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.8 %

Procedure:
A stirred mixture of 4-methyl-3-oxo-5α-4-azaandrostan-17-carboxaldehyde (0.952 g, 3.0 mM), hydroxylamine hydrochloride (1.10 g, 15.8 mM), anhydrous pyridine (6 mL) and anhydrous ethanol (12 mL) was refluxed gently under a nitrogen atmosphere for 6.3 hours. After cooling, the ice-cooled mixture was diluted, with stirring, with a slight excess of chilled dilute hydrochloric acid (ca. 0.3N), the suspension aged for ca. 20 minutes, filtered, washed with water and dried to give (38) 0.855 g. MS M+ calcd for C20H32N2O2 332.48, observed m/e 332.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1>>[N:1]1[NH:2][N:3]=[C:15]([C:11]2[CH:10]=[C:9]([NH2:8])[CH:14]=[CH:13][CH:12]=2)[CH:16]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1cccc(N)c1
Product: Nc1cccc(-c2cn[nH]n2)c1
Temperature: 150 °C

Procedure:
The mixture of azidotrimethylsilane (137 μL, 1.03 mmol) and 3-amino-phenylacetylene (117 mg, 1.00 mmol) was heated in a sealed tube at 150° C. for 16 h. After that time, the mixture was cooled down and triturated by EtOAc/hexane (50%, 10 mL). The mother liquor was purified by TLC eluting with 7% MeOH/CH2Cl2. to give the title compound as brown oil. 1H NMR (CD3OD, 400 MHz): δ=6.61-6.64 (m, 1H), 7.01-7.09 (m, 3H), 7.94 (s, 1H). MS (ES+): m/z 161.20 (38) [MH+]. HPLC: tR=1.54 min (ZQ2000, polar—5 min).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[Br:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[C:14]([Br:24])[CH:13]=[CH:12][CH:11]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1cnc2ccccc2c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Brc1cnc2cccc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To concentrated H2SO4 (130 mL) was added dropwise at 0° C., over 80 min, 3-bromoquinoline (50 g) at a rate allowing the internal temperature to be maintained between 0° and 10° C. After the addition was complete, NBS (48 g) was added portionwise and the reaction mixture was stirred at rt overnight. The reaction mixture was poured onto ice (2 L) and the resulting solid was dissolved in DCM (600 mL). The aq. layer was further extracted with DCM (600 mL) and the combined extracts were washed with 1M NaOH (300 mL) and concentrated in vacuo. The residue was adsorbed on SiO2 and the resulting dispersal was loaded on the top of a column and eluted with a DCM-Hex (1-1, 3 L), then DCM (3 L) and finally DCM-ether (1-1, 2 L). The title compound was recovered from the last fraction after evaporation to yield 40 g of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=3)[C:11](=[O:32])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].[Br:33]Br>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:33])[N:12]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:31])[F:30])[CH:22]=3)[C:11](=[O:32])[NH:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: BrBr
Reactant: CCOC(=O)C1=C(C)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(CBr)N(c2ccc(F)c(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-(4-cyanophenyl)-1-[4-fluoro-3-(trifluoromethyl)phenyl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (447 mg, 1.0 mmol) was dissolved in chloroform (10 ml) and bromine (176 mg, 1.10 mmol) was added at 0° C. The ice bath was removed and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was then diluted with chloroform (20 ml) and washed successively with 10% strength aqueous sodium thiosulphate solution (10 ml) and concentrated aqueous sodium chloride solution (10 ml). The organic phase was separated off, dried over sodium sulphate, filtered and concentrated on a rotary evaporator. This gave 570 mg (quant.) of the target compound which was reacted further without further purification.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.[CH:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[C:13]=2[CH:12]=[CH:11][N:10]=1>O1CCCC1>[CH:16]1[CH:17]=[C:18]2[C:13](=[C:14]([S:19]([N:1]3[CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7]3)(=[O:21])=[O:20])[CH:15]=1)[CH:12]=[CH:11][N:10]=[CH:9]2
Reactant: C1CNCCNC1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: Cl
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2cnccc12)N1CCCNCC1
Temperature: -5 °C
Yield: 41.1 %

Procedure:
Homopiperazine (3.413 g) was dissolved in tetrahydrofuran (57 ml) with stirring. After cooling the solution to −5° C., 5-isoquinolinesulfonyl chloride hydrochloride (3.00 g) was added while maintaining the internal temperature at 10° C. or less. The mixture was stirred at 5° C. or less for four hours. The reaction mixture was allowed to stand to reach room temperature and filtered to remove insoluble matter. The filtrate was concentrated under reduced pressure, followed by the addition of ethyl acetate (57 ml), water (17 ml), and 3 N hydrochloric acid aqueous solution (6.4 ml). The mixture was separated into layers to obtain a water layer. After washing the water layer with ethyl acetate (7 ml), water (6 ml), ethyl acetate (57 ml), and 6 N sodium hydroxide aqueous solution (3 ml) were added to separate the mixture into layers and obtain an organic layer. The organic layer was concentrated under reduced pressure and the residue was dried under reduced pressure to obtain fasudil (1.36 g). The yield was 41%. The fasudil is processed by the method described in JP-A-9-71582 to obtain fasudil hydrochloride.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[C:6]([O:9][CH2:10][C@@H:11]1[CH2:16][CH:15]=[CH:14][CH2:13][C@@H:12]1CO)(=[O:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:6]([O:9][CH2:10][C@@H:11]1[CH2:12][CH:13]=[CH:14][CH2:15][C@@H:16]1[CH2:2][Br:5])(=[O:8])[CH3:7]
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)OC[C@@H]1CC=CC[C@@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)OC[C@@H]1CC=CC[C@@H]1CBr
Reaction time: 96 h

Procedure:
To a solution of dichloromethane (20 mL), tetrabromomethane (1.5 eq) and 1(R)-acetoxymethyl-2(S)-hydroxymethylcyclohex-4-ene (6.8 mmol) was added a solution of triphenylphosphine (1.2 eq) in dichloromethane (5 mL) and the reaction stirred in the dark for four days. The reaction was concentrated to a dark oil and triturated with ether. The solid was filtered and the filtrate concentrated and purified by silica gel chromatography to yield the desired compound as a colorless oil. 1HNMR (500 mHz), CDCl3): 5.64 ppm (dd, 2H), 4.09-4.0 (m, 2H); 3.48 (dd, 1H); 3.38 (t, 1H); 2.08 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][OH:4].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:1][C:2]([CH3:12])([CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:3][O:4][S:14]([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)CN1CCCCC1
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 0.51 g (2.99 mmol) of 2,2-dimethyl-3-piperidin-1-yl-propan-1-ol in 7 ml of dichloromethane was treated at 0° C. with 0.24 ml (179.59 mmol) of methanesulfonyl chloride and stirred at RT for 2.5 h. The reaction was extracted with aqueous saturated NaHCO3 /Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, dried over Na2SO4 and evaporated to give 0.85 g (quantitative) of the title compound as light brown oil. MS: 249.2 (M+).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=1)[N:7]=3.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[CH:35]1>>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:37]5[N:36]=[CH:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCOC2CCCCO2)cn1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(-c3cn(CCO)cn3)cc1OCC2

Procedure:
5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazole to give 229 after THP-removal with aqueous HCl purification by reverse phase HPLC (49 mg). LCMS: 421.2
Reaction SMILES: [Br:1][C:2]1[C:20]([F:21])=[CH:19][C:5]([C:6]([C:8](=[CH:14][NH:15][CH:16]2[CH2:18][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](F)[C:3]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][C:20]=1[F:21]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Br)c(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(Br)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In 175 ml of dimethyl sulfoxide was dissolved 35.0 g of ethyl 2-(4-bromo-2,5-difluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate, and 27.4 g of potassium carbonate was added to the solution, after which the resulting mixture was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature, and 1,000 ml of water was then added thereto, after which the crystals formed were collected by filtration, to obtain 30.0 g of colorless, crystalline ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:34][O:35][C:36]1[C:41]([CH2:42][OH:43])=[CH:40][CH:39]=[CH:38][N:37]=1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][C:54](O)=[CH:53][CH:52]=2)=[CH:47][CH:46]=1>C1COCC1>[Br:44][C:45]1[CH:46]=[CH:47][C:48]([C:51]2[CH:56]=[CH:55][C:54]([O:43][CH2:42][C:41]3[C:36]([O:35][CH3:34])=[N:37][CH:38]=[CH:39][CH:40]=3)=[CH:53][CH:52]=2)=[CH:49][CH:50]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COc1ncccc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ncccc1COc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of PPh3 (0.53 g, 2.03 mmol) and DIAD (0.4 mL, 2.03 mmol) in dry THF (3 mL) at 0° C. was added a mixture of (2-methoxy-pyridin-3-yl)-methanol (0.18 g, 1.27 mmol) from Step A and 4′-bromo-biphenyl-4-ol (0.33 g, 1.33 mmol) in dry THF (2 mL). After 1 hr, the reaction was warmed to room temperature and monitored by TLC. After the reaction was completed (˜4 h), the reaction mixture was concentrated under vacuo and then diluted with EtOAc. The precipitates were filtered. The filtrate was brought to the usual work-up. The resulting crude product was purified by chromatography (silica gel, 15% EtOAc/hexanes) to give the titled compound. MS: 370, 372 (M+H)+.
Reaction SMILES: [C:1]([S:5](/[N:7]=[CH:8]/[CH2:9][C:10]1([C:23](OC)=[O:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[C:27]1([Li])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC>[C:1]([S:5]([N:7]1[CH:8]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:9][C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[C:23]1=[O:24])=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: [Li]c1ccccc1
Reactant: COC(=O)C1(C/C=N/S(=O)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccccc1)N(S(=O)C(C)(C)C)C2=O
Temperature: 0 °C
Yield: 12.5 %

Procedure:
To a −78° C. solution of 1-tert-butyl 4-methyl 4-{(2E)-2-[(tert-butylsulfinyl)imino]ethyl}piperidine-1,4-dicarboxylate (358 mg, 0.921 mmol) in ether (10 mL) was added phenyllithium (1.8 M, 1.6 mL, 3.1 mmol). The reaction was warmed to 0° C. After 1 h the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with dichloromethane (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 2 to 55% ethyl acetate:hexanes to give the title compound (50 mg). MS: m/z=435.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([O:12][Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc(O)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)CCC(=O)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reaction time: 5 h

Procedure:
To a solution of compound XIV (2.00 g, 10.5 mmol) in dimethylformamide (16 mL) was added tertbutyldimethylsilyl chloride (1.90 g, 12.6 mmol) and imidazole (1.79 g, 26.3 mmol) at room temperature. After 5 hours, 5% NaHCO3 (50 mL) was added and the mixture was extracted with hexane (2×75 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3.22 g (Y: 99%) of the title compound; 1H-NMR (CDCl3): δ7.44 (d, J=2.8 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H), 7.01 (dd, J=8.7, 2.8 Hz, 1H), 2.71 (t, J=7.0 Hz, 2H), 1.99 (t, J=7.0 Hz, 2H), 1.36 (s, 6H), 0.98 (s, 9H), 0.20 (s, 6H); MS (DCI) m/e: 305 (MH+).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].I[C:16]1[N:17]=[C:18]([CH3:21])[S:19][CH:20]=1>>[CH3:21][C:18]1[S:19][CH:20]=[C:16]([C:5]#[C:4][CH2:3][CH2:2][C:1]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[O:6])[N:17]=1
Reactant: Cc1nc(I)cs1
Reactant: C#CCCC(=O)Oc1ccccc1Cl
Product: Cc1nc(C#CCCC(=O)Oc2ccccc2Cl)cs1
Yield: 33.9 %

Procedure:
According to the protocol described in Example 237(B), the reaction between 2-chlorophenyl pent-4-ynoate (compound 160(A), 290 mg, 1.40 mmol) and 4-iodo-2-methylthiazole (315 mg, 1.40 mmol) afforded 145 mg of 2-chlorophenyl 5-(2-methylthiazol-4-yl)pent-4-ynoate (Yield: 34%) as yellow-oil.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=O)[CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[S:23])[CH2:8][CH2:9][NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CCNc2cc(Br)ccc2N1
Solvent: C1CCOC1
Product: S=C1CCNc2cc(Br)ccc2N1
Yield: 74.7 %

Procedure:
A solution of 7-bromo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (3) (1.5 g, 6.25 mmol) and Lawesson's Reagent (2.5 g, 12.5 mmol) in THF (50 mL) was heated at 80° C. overnight. The mixture was evaporated, water (50 mL) was added and the solution was extracted with ethyl acetate (100 mL), washed with water (50 mL), dried and concentrated to give the residue, which was purified by CombiFlash (PE:EA=5:1) to afford 7-bromo-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (1.2 g, yield 75%). LRMS (M+H)+: 256 m/z. 1H NMR (300 MHz, CDCl3) δ 3.13-3.17 (t, J=5.4 Hz, 2H), 3.75-3.79 (t, J=5.4 Hz, 2H), 6.77-6.80 (m, 1H), 6.95-6.98 (m, 2H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[N+:9]([O-:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]1[CH2:17][CH2:16][CH:15]=[CH:14][CH:13]=1>>[CH2:7]([C@@H:8]1[C@@H:17]2[CH:12]=[CH:13][CH2:14][CH2:15][C@@H:16]2[O:11][N:9]1[CH3:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1=CCCC=C1
Reactant: C[N+]([O-])=CCc1ccccc1
Product: CN1O[C@H]2CCC=C[C@H]2[C@H]1Cc1ccccc1
Temperature: 25 °C
Yield: 87 %

Procedure:
N-(2-Phenylethylidene)methylamine N-oxide (797 mg, 5.34 mmol) and 1,3-cyclohexadiene (3 ml) were heated together at 70° C. in a sealed tube under nitrogen for 14 hours. The solution was cooled to room temperature and the excess 1,3-cyclohexadiene was removed under reduced pressure to yield a viscous oil (1.07 g, 87%). This crude product was purified by flash chromatography using 60:40 v/v petroleum ether (fraction of bp 40°-60° C.):ethyl acetate as the solvent system to give the title compound (Rf=0.34) as a pale yellow oil (375 mg, 35%), υmax (film) 3030, 2920, 2840, 1605, 1495, 1455, 1090 cm-1 ; δH (400 MHz; CDCl3 -Me4Si) 1.80-2.00 (4H, br m), 2.20-2.25 (1H, m), 2.60-2.65 (3H, s), 2.75-2.95 (2H and 1H, m), 4.20-4.25 (1H, br), 5.6-6.0 (2H, br m), 7.20-7.30 (5H, br m); M/z 229 (MH+ 100%) (Found: MH+ 230.1545; C15H19NO requires MH+ 230.1574).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:25])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:14]
Reactant: COc1n[nH]c2cc(Br)ccc12
Reactant: CCOC(=O)C=Cc1ccccn1
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1ccccn1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-pyridin-2yl-acrylic acid ethyl ester CCXLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-pyridin-2-yl-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Cl[C:13]([F:20])([F:19])C(OCC)=O.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH:13]([F:20])[F:19]
Reactant: O=[N+]([O-])c1ccc(Br)c(O)c1
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Br)c(OC(F)F)c1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a N2 purged round bottom flask was added 2-bromo-5-nitrophenol (29.0 g, 133 mmol, 1.0 eq.) followed by 16.8 mL (133 mmol, 1.0 eq) of ethyl chlorodifluoroacetate and 18.8 g of K2CO3 (133 mmol, 1.0 eq.). Anhydrous DMF (300 mL) was added and the mixture was stirred at 70° C. for 5 h. The mixture was cooled to RT and the solvent was removed. The obtained crude mixture was dissolved in CH2Cl2 (500 mL) and washed with 1 N NaOH (aq.). The organic layer was dried (MgSO4), filtered and evaporated. The crude material was further purified by column chromatography (0-5% EtOAc in hexanes) providing pure 1-bromo-2-difluoromethoxy-4-nitro-benzene.