Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[SH-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1Cl.Cl>CO>[Cl:4][C:5]1[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][C:10]=1[SH:2]
Reactant: [SH-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(S)c(Cl)c1
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A solution of sodium hydrosulfide hydrate (60 g technical; ~0.75 mol) in methanol (200 ml) is added to a solution of 3,4-dichloronitrobenzene (100.0 g; 0.52 mol) in methanol (750 ml) with cooling and at a rate to maintain the temperature of the reaction mixture below 40° C. After the addition is completed, the reaction mixture is stirred an additional 16 hours, and then poured on a mixture of ice and hydrochloric acid. The mixture remains strongly acidic. The precipitated yellow solid is filtered, washed and dried. This solid is purified by dissolving same in 25% aqueous sodium hydroxide, extracting the resultant solution several times with methylene chloride until the methylene chloride solution remains colorless. Next, concentrated hydrochloric acid is added to the aqueous solution dropwise to precipitate a light yellow solid and adjust the pH to 1-2. The thus formed slurry is filtered, the isolated solid is washed with water and dried to afford 52.6 g (55%) of title compound. A sample is recrystallized from cyclohexane, m.p. 77°- 78° C. Lit. 73.5°-74° C. (ref. Nippon Kagaku Kaishi 1972, 756).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(N=C=NC2CCCCC2)CCCC[CH2:13]1.N1C=CC=CC=1.C(O)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-Hydroxyphenylacetic acid (10 g, 65.7 mmol) and 1,3-dicyclohexylcarbodiimide (DCC, 16.27 g, 78.8 mmol) in DMF (30 ml) was added pyridine (2.5 ml) followed by absolute ethanol (15 ml, 255.5 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered, concentrated and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: NC(=NO)[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:21](C1C=C(C=CC=1)CO)#[N:22]>>[C:21]([C:18]1[CH:17]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH2:7][O:8][CH2:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])#[N:22]
Reactant: CC(C)(C)OC(=O)COCc1ccc(C(N)=NO)cc1
Reactant: N#Cc1cccc(CO)c1
Product: CC(C)(C)OC(=O)COCc1cccc(C#N)c1

Procedure:
The title compound was prepared following the procedure described for Intermediate 15 Step 1, but starting from 3-cyanobenzyl alcohol. It was obtained as a colorless oil (4.4 g, 78%). HPLC (Method A) Rt 4.55 min (Purity: 98.3%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:10][C:11]1[C:12]([N:22]([CH2:27][CH:28]2[CH2:30][CH2:29]2)[CH2:23][CH:24]2[CH2:26][CH2:25]2)=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[C:8]#[N:9].[N-:40]=[N+:41]=[N-:42].[Na+].[Cl-].[NH4+]>CN(C=O)C>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:10][C:11]1[C:12]([N:22]([CH2:23][CH:24]2[CH2:25][CH2:26]2)[CH2:27][CH:28]2[CH2:30][CH2:29]2)=[N:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[C:8]1[N:40]=[N:41][NH:42][N:9]=1
Reactant: Cc1cccc2cc(CN(C#N)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c(N(CC3CC3)CC3CC3)nc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nn[nH]n3)c(N(CC3CC3)CC3CC3)nc12
Temperature: 25 °C
Yield: 98.2 %

Procedure:
N-(3,5-Bis(trifluoromethyl)benzyl)-N-((2-(bis(cyclopropylmethyl)amino)-8-methylquinolin-3-yl)methyl)cyanamide (0.118 g, 0.216 mmol), sodium azide (0.70 g 1.08 mmol) and ammonium chloride (0.058 g, 1.08 mmol) were put in a RB flask under N2 atmosphere. To this reaction mixture, DMF (2 mL) was added and was refluxed for 1 h. The reaction mixture was cooled to RT and ice was added to this and extracted with ethylacetate (3×10 mL). The combined organic layer was washed with brine, dried over sodium sulphate and then concentrated under vacuum to afford of (3-{[(3,5-bistrifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-methyl}-8-methyl-quinolin-2-yl)-bis-cyclopropylmethyl-amine as a yellow solid (0.125 g, 99%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([C:18]1[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=1)[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:10]([O:9][C:8]([N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1)[C:18]1[N:19]=[CH:20][C:21]([O:24][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:22][N:23]=1)=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(OCc1ccccc1)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OCc2ccccc2)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-carbamate (9.70 g) and ethyl 4-bromobutyrate (3.53 g) are dissolved in N,N-dimethylformamide (50 mL) and thereto is added potassium carbonate (3.41 g) and the mixture is stirred at 50° C. for 1 hour. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (8.29 g). MS (m/z): 586 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](O)(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.O=S(Cl)[Cl:17]>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:17])(=[O:10])=[O:9])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1

Procedure:
In a similar fashion using route 39 general procedure 96, 4-methyl-2-nitro-benzenesulfonic acid 448 (6.2 g, Salt form), SOCl2 (15 ml) and DMF (0.28 ml) gave the title compound (3.10 g) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:21]([NH:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])(=O)[CH3:2].[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C.[B-]C#N.[Na+]>C(Cl)Cl.CO.[Ti](Cl)(Cl)(Cl)Cl>[CH3:28][N:26]([CH3:27])[CH2:25][CH2:24][NH:23][C:21]([C:6]1[CH:7]=[C:8]2[C:13](=[C:4]([CH:1]([NH:34][C:33]3[CH:35]=[CH:36][C:30]([F:29])=[CH:31][CH:32]=3)[CH3:2])[CH:5]=1)[O:12][C:11]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[CH:10][C:9]2=[O:20])=[O:22]
Reactant: Nc1ccc(F)cc1
Reactant: CC(=O)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [B-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)NCCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 23 °C
Reaction time: 48 h
Yield: 58.2 %

Procedure:
Titanium(IV) chloride (0.129 mL, 0.13 mmol) was added to a stirred suspension of 8-acetyl-N-(2-(dimethylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (100 mg, 0.26 mmol), 4-fluoroaniline (0.042 mL, 0.44 mmol) and triethylamine (0.108 mL, 0.77 mmol) in DCM (2 mL) under nitrogen at 10° C. The resulting solution was stirred at 23° C. for 2 days. A saturated solution of sodium carbonate was added and extracted with DCM. The organic phase was washed with water, brine, dried over magnesium sulfate, and concentrated to afford the crude imine. The imine was diluted with DCM and MeOH, and acetic acid (0.030 mL, 0.52 mmol) and sodium cyanotrihydroborate (32.4 mg, 0.52 mmol) were added. The resulting solution was stirred at room temperature for 30 min. A solution of sodium carbonate was added and extracted with DCM. The organic phase was washed with water, brine, dried over magnesium sulfate, and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 5% methanol in DCM followed by 5% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness and a second purification was done on a preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to give a white solid which was triturated in MTBE then dried under vacuum to afford N-(2-(dimethylamino)ethyl)-8-(1-(4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (73.0 mg, 58.6%). Mass Spectrum: M+H+ 483. NMR Spectrum: (CDCl3) 1.60 (d, 3H), 2.25 (s, 6H), 2.50 (t, 2H), 3.45-3.58 (m, 6H), 3.79-3.89 (m, 4H), 4.02 (bs, 1H), 4.88-4.98 (m, 1H), 5.56 (s, 1H), 6.40 (dd, 2H), 6.81 (dd, 2H), 6.91 (bs, 1H), 8.27 (d, 1H), 8.34 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13](O)=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.S(Cl)(Cl)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:16])=[C:11]([C:13]([N:25]=[N+:26]=[N-:27])=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1oc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carboxylic acid (30a) (750 mg, 2.54 mmol) and thionyl chloride (12.68 mmol) were refluxed at 100° C. for 20 h. Thionyl chloride was removed under reduced pressure. The resulting solid acid chloride was dissolved in acetone (15 mL) and cooled to 0° C. Sodium azide (7.61 mmol) dissolved in water (3 mL) was added to the reaction mixture at 0° C. and stirred for 30 min. The reaction temperature was raised to room temperature and stirred for 5 h. The reaction mixture was concentrated to remove the solvent. The compound precipitated in the aqueous layer was filtered and dried under vacuum to obtain the desired compound 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-5-methyloxazole-4-carbonyl azide. LC/MS: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O: 0.1% TFA; Solvent B=90% MeOH: 10% H2O: 0.1% TFA; gradient 0-100% B over 2 min (3 min run time); retention time: 2.363 min.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10](O)[CH3:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([Cl:22])(=O)=O)=CC=1.O>N1C=CC=CC=1>[Cl:22][CH:10]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=1)[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)c1cc(C(C)(C)C)on1
Solvent: O
Solvent: c1ccncc1
Product: CC(Cl)c1cc(C(C)(C)C)on1
Reaction time: 5 h

Procedure:
1.18 g of 1-(5-t-butyl-isoxazol-3-yl)ethanol was dissolved in 2 ml of pyridine, and 1.36 of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.60 g of 3-(1-chloroethyl)-5-t-butylisoxazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH2:34][C@@H:35]([CH2:44][CH2:45][S:46][CH3:47])[C:36]([O:38][CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[C:20]([CH:24]=2)[C:21]([NH:34][C@@H:35]([CH2:44][CH2:45][S:46][CH3:47])[C:36]([O:38][CH:39]2[CH2:40][CH2:41][CH2:42][CH2:43]2)=[O:37])=[O:22])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: CSCC[C@H](N)C(=O)OC1CCCC1
Reactant: O=C(O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Product: CSCC[C@H](NC(=O)c1cc(OC(Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1)C(=O)OC1CCCC1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 5-(1-(4-fluorophenyl)-2-(imidazol-1-yl)ethoxy)-2-(4-fluorophenethyl)benzoic acid and cyclopentyl (2S)-2-amino-4-(methylsulfanyl)butanoate (L-methionine cyclopentyl ester) by a similar method to that used for Example 34.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][C:8]=1[Cl:17])C.C(C1C=C(S[CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[O:36][C:35]=2[CH3:49])C=CC=1OCC(O)=O)C>>[Cl:17][C:8]1[CH:9]=[C:10]([S:13][CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:40]=[CH:41][C:42]([C:45]([F:48])([F:46])[F:47])=[CH:43][CH:44]=3)[O:36][C:35]=2[CH3:49])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:3])=[O:18]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: CCc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CSc1ccc(OCC(=O)O)c(Cl)c1

Procedure:
The title compound was prepared from ethyl[4-(chlorosulfonyl)-2-chlorophenoxy]acetate (intermediate 113) by a method analogous to that used for the preparation of {2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetic acid (example 145).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1(C)C=CC=CC=1>[C:16]1([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and acondenser, 31.3 g (0.2 mol) of 2-chlorobenzoic acid and 180 g of toluene are placed. To the above mixture in the flask, 25.0 g (0.21 mol) of thionyl chloride is added dropwise over 30 minutes while stirring at a temperature of from 60° to 65° C. to be allowed to react with each other for about 30 minutes. To the above reaction mixture, a solution containing 27.9 g (0.3 mol) of aniline dissolved in 100 g of toluene is dropwise added to be allowed to react with each other at a temperature of from 70° to 75° C. for 30 minutes. After completion of the reaction, the reaction mixture is cooled to room temperature, and 70 g of a 5% by weight hydrochloric acid solution is added to the above mixture. The mixture is vigorously shaken and kept standing for separation of the toluene layer from the aqueous layer. Afterseparation of the toluene layer, it is condensed to precipitate white crystals, followed by recrystallization (in a water/methanol mixture of 3/7), to give 43.1 g of N-phenyl-2-chlorobenzamide (melting point: 116° to 117° C.). The yield of the product against 2-chlorobenzoic acid is 93%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH:20]=[O:21])[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][OH:21])[CH:9]=[CH:8][C:7]=1[Cl:22])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2C=O)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CO)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
To [5-(4-bromo-2-formyl-phenoxy)-2-chloro-phenyl]-acetic acid ethyl ester (0.3 g, 0.76 mmol) in MeOH (20 mL) was added sodium borohydride (0.03 g, 0.78 mmol), and the mixture was stirred at room temperature for 10 minutes. The mixture was worked-up to give the desired product (0.3 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].O[CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>Cl>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[CH2:7][S:5][CH2:4][CH2:3][NH2:2]
Reactant: NCCS
Reactant: OCc1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCSCc1cccs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(b)(i) Cysteamine hydrochloride (9.95 g) was dissolved in concentrated hydrochloric acid (50 ml) and the solution was cooled to 0°. 2-Hydroxymethylthiophene (10 g) was added dropwise to the stirred solution which was maintained at below 5°. The mixture was stirred overnight at room temperature, adjusted to pH 10 with concentrated aqueous sodium hydroxide and extracted with ethyl acetate. The extracts were evaporated and the residue was distilled at 158°-164°/760 mm Hg to give 2-(2-thienylmethylthio)-ethylamine which was converted into the hydrochloride, m.p. 108°-111°, by treatment with ethanolic HCl and ether.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[CH2:5][CH2:4][N:3]=1.O.O.[Sn](Cl)Cl.O.[OH-].[K+]>C(O)C.Cl>[NH2:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][N:3]=[C:2]2[CH3:1])=[CH:7][CH:8]=1
Reactant: CC1=NCCc2ccc([N+](=O)[O-])cc21
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC1=NCCc2ccc(N)cc21
Yield: 55.3 %

Procedure:
(±) 1-Methyl-7-nitro-3,4-dihydroisoquinoline (2.0 g, 10.5 mmol) was dissolved in ethanol (150 ml) and heated to 60° C., before treatment with a solution of tin (II) chloride dihydrate (9.5 g, 42.1 mmol) in conc. HCl (30 ml). The resultant mixture was heated at 60° C. for 1 h. After cooling, the reaction mixture was poured into water (200 ml) and basified (pH 9) with KOH pellets, liberating an oily residue. This residue was extracted into dichloromethane and dried over magnesium sulfate. Purification by chromatography through silica gel, eluting with (0.5% 0.88 NH3: 4.5% CH3OH: 95% CH2Cl2) yielded the title compound as a dark brown oil (0.93 g, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]Br)=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[C-:19]#[N:20].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:5][CH:6]=[CH:7][C:8]=1[CH2:9][C:19]#[N:20]
Reactant: COc1c(CBr)cccc1Oc1ccc(Cl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccc(Cl)cc1
Yield: 94.8 %

Procedure:
A solution of 4-chlorophenyl 2-methoxy-3-bromomethylphenyl ether (14.9 g) in dimethyl sulfoxide (40 ml) and powdered sodium cyanide (2.3 g) were treated in a similar manner to that of Example 5-(4) to give oily 2-[2-methoxy-3-(4-chlorophenoxy)phenyl]acetonitrile (11.8 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:9]([CH2:12][S:13]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18]C2)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Na+].BrC1C=CC(CS([O-])(=O)=O)=C(C(OC)=O)C=1OC.N1CCCC1>>[Br:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:9]([CH2:12][S:13]([N:16]2[CH2:18][CH2:19][CH2:20][CH2:21]2)(=[O:14])=[O:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(CS(=O)(=O)N2CCCCC2)ccc(Br)c1OC
Agent: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Agent: [Na+]
Solvent: C1CCNC1
Product: COC(=O)c1c(CS(=O)(=O)N2CCCC2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 147, starting from methyl (4-bromo-3-methoxy-2-methoxycarbonylphenyl)-methanesulphonic acid sodium salt (Intermediate 148) and pyrrolidine as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CC#N>[CH3:20][S:21]([O:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)(=[O:23])=[O:22]
Reactant: Oc1ccc(-c2cccs2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)Oc1ccc(-c2cccs2)cc1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To a mixture of 4-(2-thienyl)phenol (1.76 g) and triethylamine (1.50 g) in MeCN (10 ml) was added dropwise methanesulfonylchloride (1.26 g) with ice-cooling. The mixture was stirred for 1 hour, then for 1 hour at ambient temperature. The resulting mixture was concentrated and diluted with a mixture of AcOEt and H2O to separate solid. The separated solid was recovered and washed with H2O and AcOEt to give 1.62 g of 2-(4-methanesulfonyloxyphenyl)thiophene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[C@H:9]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)[C@H:10]([CH3:18])[CH2:11][O:12][CH2:13][C:14](OC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C@@H:9]([N:8]([CH3:24])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[C@H:10]([CH3:18])[CH2:11][O:12][CH2:13][CH2:14][OH:15]
Reactant: COC(=O)COC[C@@H](C)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](COCCO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of compound 2.7a (0.95 g, 2.78 mmol) in methanol (7 mL) was added sodium borohydride (1.05 g, 27.8 mmol, 10.0 equiv) at 0° C. After stirring for 1 hour, the reaction was quenched with 1.0 M sulfuric acid and extracted with DCM. Combined organic layer was dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound 2.8.1a (0.85 g) which was used for the next step without further purification. MS m/z (M+Na) 336.3