Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[C:13]([N:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH:17]2[CH2:25][N:26]([CH3:29])[CH2:27][CH2:28][CH:16]12)#[CH:14].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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>[CH3:29][N:26]1[CH2:27][CH2:28][C:16]2[N:15]([C:13]#[C:14][C:2]3[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=3)[C:23]3[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[C:17]=2[CH2:25]1
Reactant: C#CN1c2ccc(C)cc2C2CN(C)CCC21
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CNC(=O)c1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-fluoro-N-methyl-benzamide (100 mg, 0.5 mmol), 5-ethynyl-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (123 mg, 0.5 mmol), dichlorobis(triphenylphosphine)palladium(II) (17 mg, 0.25 mmol) and TBAF.3H2O (475 mg, 1.5 mmol) were mixed and stirred at 80° C. for 30 min under nitrogen. The progress of reaction was monitored by TLC and LCMS. The mixture was cooled to RT, water was added, and extracted with EtOAc. The organic layer was washed with water (1×10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by column chromatography using silica (100-200 mesh) and 0-2% MeOH:DCM as eluent. 1H NMR (CDCl3, free base) δ (ppm): 8.10 (t, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 7.18 (m, 2H), 6.70 (bs, 1H), 3.95 (m, 2H), 3.20 (m, 4H), 3.05 (d, 3H), 2.80 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[C:18]([O:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:27](=[O:28])[CH2:26][NH:25][C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
L-proline methylester hydrochloride (13.6 g, 82.7 m mole) was suspended in chloroform (200 ml) and to the suspended solution triethylamine (8.3 g, 82.7 m mole) was added while cooling. To the solution, N-t-butyloxycarbonyl glycine (14.5 g, 82.7 m mole) was added and WSC hydrochloride (15.82 g, 82.7 m mole) was gradually added thereto while cooling with ice. The reaction was carried out for 2 hours while cooling with ice, and next overnight at room temperature. The reaction solution was washed with 10% citric acid, aqueous sodium chloride, 5% sodium bicarbonate and aqueous sodium chloride in order, and dried with anhydrous sodium sulfate. The solution was distilled under reduced pressure leaving a syrupy N-t-butyloxycarbonylglycyl-L-proline methylester product (22.5 g, 78.5 m mole, yield: 95%). This product gave a single spot with Rf =0.48 by silica gel thin layer chromatography (developing solvent, benzene:ethyl acetate=1:1, colour forming method: spraying of 25% hydrobromic acid and 0.1% ninhydrin and heating).
Reaction SMILES: [BH3-]C#N.[Na+].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2>C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CCN2
Reaction time: 2 h

Procedure:
NaBH3CN (19.3 g, 0.3061 mol) was added in 3 portions to a cooled (15° C.) solution of 5-bromoindole (20 g, 0.10 mol) in glacial acetic acid (500 mL) and stirred for 2 h at this same temperature. The reaction mixture was quenched with water, cooled and basified with a sodium hydroxide pellet. It was then extracted with diethyl ether. The organic layer was washed with water and brine, dried over sodium sulfate, concentrated and purified by column chromatography over silica gel to give the sub-title compound as a pale yellow solid. Yield: 20 g.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Cl:25][CH2:26][C:27]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:28]
Reactant: Cc1cccc(C)c1NCC=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1cccc(C)c1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The diethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde (13 grams), benzene (50 ml) and sodium carbonate (5.8 grams) dissolved in water (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel. The mixture was cooled in an ice bath and chloroacetyl chloride (6.2 grams) was added dropwise with stirring. After addition was completed stirring was continued and the reaction mixture was allowed to warm up to room temperature. After this time the mixture was filtered and the filtrate washed with dilute aqueous hydrochloric acid. The washed filtrate was dried over anhydrous magnesium sulphate and was stripped of solvent under reduced pressure to yield the desired product the diethyl acetal of 2-[N-(α-chloroacetyl)-2,6-dimethylanilino]acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:15]O.C(O)=O>O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
4-chlorobenzaldehyde (50 g; 0.36 mol), sodium formate (48.4 g; 0.71 mol), and hydroxylamine hydrochloride (24.7 g; 0.36 mol) were added to 400 ml formic acid (98 wt.%). The reaction mixture was refluxed for 1 hour at l30.C, cooled to room temperature and poured into 1 liter cold water to produce a white precipitate, which was filtered and air-dried to yield 43 g 4-chlorobenzonitrile (m.p.=91°-92° C). The yield for this step in the reaction sequence was about 88%.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([OH:24])(=[O:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:1][NH:2][C@@H:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]([C:13]2[CH:14]=[CH:15][C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=2)[CH2:5][CH2:4]1.[C:21]([O-:24])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: Cc1ccccc1
Product: CC(=O)[O-]
Temperature: 25 °C

Procedure:
30 gms of sertraline base is dissolved in 200 ml of toluene under stirring at room temp. 5 ml acetic acid is added to the clear toluene solution and stirred for 1 hr. at 25° C. to obtain a thick white precipitate. The solids are filtered and re-slurried in 100 ml toluene for 30 minutes and filtered. The product is dried under vacuum at 60° C. for 5-6 hours to give sertraline acetate.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:33])(=[O:32])[CH3:31].C(OC)(C)(C)C>C(O)CCC>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:33])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(=O)[O-]
Temperature: 20 °C

Procedure:
Sunitinib base (3 g) was suspended in n-butanol (15 ml) with stirring at 20° C., then 1.05 eq (0.45 ml) of acetic acid were added observing dissolution and after 1-2′precipitation of an orange solid. The mixture was heated to 60° C. and other 6 ml of n-butanol were added. Then methyl tert-butyl ether (60 ml) was added at 60° C. within 10 min with stirring, the mixture was cooled to −10° C. in 2 hours. After 1 h at −10° C. the solid was filtered, washed with 2×20 ml of MTBE and dried on the filter for 1 h.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].C(O)(C)C.[C:14]([OH:17])(=[O:16])[CH3:15]>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:14]([O-:17])(=[O:16])[CH3:15]
Reactant: CC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CC(C)O
Solvent: O
Product: CC(=O)[O-]

Procedure:
78 g (1 equivalent) of metformin free base, 234 Ml of isopropanol, 234 Ml of water and 57 Ml (1.65 equivalents) of acetic acid were added to a reactor, and stirred. The resulting crystal was filtered and washed with isopropanol, and then dried at 60° C. to obtain 54.6 g of metformin acetate (yield: 47.8%).
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[CH:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17]3[NH:21][C:20]([C:22]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)=[C:23]4[CH:51]=[CH:50][C:25](=[C:26]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:27]5[CH:43]=[CH:42][C:29](=[C:30]([C:36]6[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=6)[C:31]6[CH:32]=[CH:33][C:34]=2[N:35]=6)[N:28]=5)[NH:24]4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=1.[Pd:58].[C]=O>ClC1C=CC=CC=1Cl>[C:52]1([C:22]2[C:20]3[NH:21][C:17](=[CH:18][CH:19]=3)[C:16]([C:13]3[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=3)=[C:34]3[N:35]=[C:31]([CH:32]=[CH:33]3)[C:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:29]3[NH:28][C:27]([CH:43]=[CH:42]3)=[C:26]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:25]3=[N:24][C:23]=2[CH:51]=[CH:50]3)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.[Pd:58]
Reactant: C1=Cc2nc1c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Agent: [Pd]
Agent: [C]=O
Solvent: Clc1ccccc1Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: C1=Cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1nc(c(-c3ccccc3)c3ccc([nH]3)c2-c2ccccc2)C=C1
Temperature: 240 °C
Yield: 78 %

Procedure:
10 g of nitrobenzene, 0.6 g of tetraphenylporphyrin and 0.1 g of palladium black are placed in the autoclave and the total volume is then brought to 100 ml by means of orthodichlorobenzene. The autoclave is scavenged with nitrogen, then 200 bars of carbon monoxide are introduced. After isolating the reactor and starting the stirring, it is heated at 240° C. for 3 and three-quarter hours, thus limiting voluntarily the progress of the reaction. After cooling analysis shows that the O.C.R. of the nitrobenzene is 33.1%. The complex is purified by operating in the same way as in Example 10. Palladium tetraphenylporphyrin is thus obtained with a yield of 78%.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C1COCC1.O.ClCCl>[OH:15][N:14]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-formylbenzoate, 37-c, (5.0 g, 30.5 mmol) and hydroxylamine hydrochloride (2.5 g, 36.6 mmol) in THF/H2O (VTHF:VH2O=4:1, 50 mL) was added sodium acetate (3.5 g, 42.7 mmol). The reaction mixture was stirred at room temperature overnight and diluted with dichloromethane (400 mL), washed with water, dried with anhydrous Na2SO4, filtrated and concentrated in vacuo to provide compound, 37-d, (4.9 g, 90%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:15][Cl:16])[CH2:10][C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>CO>[Si:1]([O:8][C@@H:9]([CH2:15][Cl:16])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C[C@H](CCl)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCl)CC=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of (R)-methyl 3-(tert-butyldimethylsilyloxy)-4-chlorobutanoate (2.13 g, 104.7 mmol) in CH3Cl2 was added dropwise DIBAL-H (120 mL, 1 M in toluene, 120 mmol) at −78° C. under N2 atmosphere. The mixture was stirred at −78° C. for 4 h. CH3OH (80 mL) was added slowly to the reaction, mixture at −78° C. Then the temperature was warmed to room temperature gradually. The mixture was filtered and the cake was washed with CH2Cl2. The combined filtrates were concentrated under reduced pressure and purified by column chromatography (PE) to give (R)-3-(tert-butyldimethylsilyloxy)-4-chlorobutanal (13 g, 60% over 2 steps). 1H NMR (300 MHz, CDCl3) δ 9.80 (t, J=1.6 Hz, 1H), 4.35-4.42 (m, 1H), 3.53 (dd, J=11.1 Hz, 4.8 Hz, 1H), 3.46 (dd, J=12 Hz, 6.3 Hz, 1H), 2.63-2.82 (m, 2H), 0.87 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21]([O:23]C)=O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[C:39]([F:41])[CH:40]=1)[NH2:37].C[Al](C)C>>[CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:12]([NH:14][N:15]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]1[C:21](=[O:23])[NH:37][C:36]1[CH:35]=[C:34]([F:33])[CH:40]=[C:39]([F:41])[CH:38]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Nc1cc(F)cc(F)c1
Agent: C[Al](C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(F)cc(F)c1
Yield: 45.8 %

Procedure:
(S)-Methyl 1-(4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanamido)-3-bromo-1H-pyrrole-2-carboxylate (4 g, 7.84 mmol) was treated with 3,5-difluoroaniline (5.06 g, 39.19 mmol) and trimethyl aluminium (2 M in toluene, 19.6 mL, 39.18 mmol) according to the method of Preparation 10a. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 2.18 g (41% yield) of the title compound as a white solid. Purity 88%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
13.8 g of 4′-fluoroacetophenone (provided from Tokyo Chemical Industry Co., Ltd.) were added in two portions to 100 ml of fuming nitric acid cooled to −10° C. with agitation. After the mixture was warmed to room temperature, the agitation was continued for further 4 hours. This mixture was poured into 1.0 liter of ice water and was extracted with 500 ml of ethyl acetate. The organic layer was dried and the solvent was distilled off under a reduced pressure. The residue was purified by a column chromatography (9/1-4/1: n-hexane/ethyl acetate) twice, whereby 4.16 g of the above-identified were obtained. Rf=0.50 (chloroform).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[S:7][C:6]([B:8]([OH:10])[OH:9])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(B(O)O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-formylthiophen-2-ylboronic acid (15.6 mg, 0.1 mmol) in MeOH (0.5 mL) was added excess amount of NaBH4. The mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure to afford crude 5-(hydroxymethyl)thiophen-2-ylboronic acid, which was used in step E without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:29]3[CH2:30][CH2:31][N:26]([C:19]4[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[S:17][N:18]=4)[CH2:27][CH2:28]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCN(c3nsc4ccccc34)CC2)C1
Yield: 58.5 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 14 using 1.0 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.88 g of 1-(1,2-benzoisothiazol-3-yl)piperazine to give 1.0 g of 6-acetyl-3-(2-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 190°-192° C. (decomposition) as an oxalate 1/2hydrate thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[C@H:31]1([NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH2:37]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:37][C@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]4[NH2:38])[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: N[C@H]1CCCC[C@@H]1N
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC[C@@H]4N)n3)c3cc(Cl)cnc32)cc1
Temperature: 140 °C

Procedure:
5-Chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 15a, (0.25 g, 0.53 mmol) and (1S,2S)-cyclohexane-1,2-diamine (0.12 g, 1.08 mmol) were dissolved in THF (3.0 mL), and heated to 140° C. for 20 minutes in a sealed vial. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (0%-15% MeOH/CH2Cl2) to provide product, 15b, as a white foamy solid (220 mg, 79% yield).
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)([OH:3])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[O:3]=[C:1]1[C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 0.25 h

Procedure:
Suspend 12 gm. of the carboxybenzyloxyphenylacetic acid of Step A in 50 ml. of trifluoroacetic anhydride in a pressure bottle and stir at 70° to 80° C. for 2.25 hours. Evaporate the reaction mixture to a syrup. Dissolve in 50 ml. of tetrahydrofuran and treat with sodium carbonate until pH 8. Stir for 15 minutes and acidify with 5 N HCl. Dilute with water and extract with ether. Wash the extract with water and dry over magnesium sulfate. Concentrate to dryness and recrystallize from ethyl acetate/hexane to obtain the title product.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].[Br:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22]Cl)=[CH:16][C:15]=1[O:24][CH3:25]>C(OCC)(=O)C.O>[Br:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22][O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:16][C:15]=1[O:24][CH3:25]
Reactant: OC1CCC1
Reactant: COc1cc(CCl)cc(OC)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(COC2CCC2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a mixture of cyclobutyl alcohol (4.16 g, 57.7 mmol) and DMF (30 mL) was added sodium hydride (60% dispersion in oil: 2.31 g, 57.7 mmol) while cooling on ice, and the mixture was stirred at room temperature for 1 hour. To this mixture was slowly added dropwise a mixture of 2-bromo-5-(chloromethyl)-1,3-dimethoxybenzene (2.47 g, 9.3 mmol) and DMF (30 mL), and the resulting mixture was stirred at room temperature for 1 hour. Water was added to the mixture while cooling on ice, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=4/1) to obtain the title compound (2.39 g, 7.94 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([SH:8])[N:3]=1.[OH-].[Na+].I[CH3:12]>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:12])[N:3]=1
Reactant: CI
Reactant: Cc1ccnc(S)n1
Agent: [Na+]
Agent: [OH-]
Product: CSc1nccc(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-Methylpyrimidine-2-thiol (79.4 g. 488 mmol) was added to 1M aqueous sodium hydroxide (NaOH) (1.02 L, 1.02 mol). To the stirring mixture was added iodomethane (76.2 g, 540 mmol) and the reaction-stirred at room temperature overnight. The mixture was extracted with dichloromethane (3×300 mL). The organic phase was dried over magnesium sulfate and concentrated to yield 66.8 g (98%) of 4-methyl-2-(methylsulfanyl)pyrimidine. 1H NMR (CDCl3): δ 8.39 (d, 1H), 6.84 (d, 1H), 2.59 (s, 3H), 2.48 (s, 3H); MS m/z 141 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:8]([C:4]2[S:3][C:2]([Br:1])=[N:6][C:5]=2[CH3:7])=[O:10])=[CH:14][CH:13]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.1 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (10.0 g, 45.0 mmol) in methylene chloride (200 mL) was added 4-fluoro-benzylamine (6.19 g, 49.5 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (21.9 g, 49.5 mmol) and N,N-diisopropylethylamine (15.7 mL, 90.1 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (300 mL), washed with water (300 mL) and brine (2×200 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide as a beige solid (13.5 g, 90% yield). MS (M+H)+=330; Rt=136 min.