Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]2)=[O:33])=[CH:4][N:3]=1.[CH3:41][N:42]([CH3:47])[C:43](=[O:46])[CH:44]=[CH2:45]>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH:35]2[CH2:40][CH2:39][CH2:38][N:37]([CH2:45][CH2:44][C:43]([N:42]([CH3:47])[CH3:41])=[O:46])[CH2:36]2)=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)NC4CCCNC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: C=CC(=O)N(C)C
Product: COc1cc(-c2csc3c(C(=O)NC4CCCN(CCC(=O)N(C)C)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
A mixture of 4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)-N-piperidin-3-ylthieno[3,2-c]pyridine-7-carboxamide (150 mg, 0.270 mmol) and N,N-dimethylacrylamide (28 mg, 0.283 mmol, 3 portions at 2 hour intervals) were reacted according to General Procedure K. The residue was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (28–30% solution) (80:20:0.05) mixture as the mobile phase to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (m, 1H), 1.51(m, 1H), 1.70 (m, 1H), 1.81 (m, 1H), 1.98 (m, 2H), 2.48 (m, 2H), 2.58 (m, 2H), 2.76 (m, 1H), 2.81 (s, 3H), 2.91 (m, 1H), 2.99 (s, 3H), 3.91 (s, 3H), 3.99 (m, 1H), 4.04 (m, 3H), 7.07 (d, 1H), 7.15 (t, 1H), 7.18 (s, 1H), 7.33 (t, 1H), 7.35 (s, 1H), 7.60 (m, 2H), 7.71 (d, 1H), 7.99 (d, 1H), 8.16 (d, 1H), 8.59 (s, 1H), 9.50 (s, 1H). LCMS (Conditions a): MH+=654.1, Rt=2.55 min.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:10])[C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:18])C(=O)C1.O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:18][C:8]1[C:9]2[O:1][CH:2]=[CH:3][C:4]=2[C:5](=[O:10])[NH:6][CH:7]=1
Reactant: O=c1[nH]ccc2occc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=c1[nH]cc(Br)c2occc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a suspension of 5H-furo[3,2-c]pyridin-4-one (11.1 g, 0.082 mol) in anhydrous acetonitrile (200 mL) was added a solution of NBS (19.0 g, 0.107 mol) in anhydrous acetonitrile (100 ml) at 0° C. over 1 h. The resulting suspension was stirred at 0° C. for 1 h and then warmed to rt for 10 min. Water (500 mL) and saturated sodium bicarbonate aqueous solution (4 ml) were added to the mixture. Off-white solids were collected by filtration and dried under vacuum to afford 7.33 g of desired product (yield: 42%). 1H NMR (DMSO-d6, 400 MHz): δ=7.06 (d, J=2.3 Hz, 1H), 7.60 (s, 1H), 8.00 (d, J=2.0 Hz, 1H). MS (ES+): 214.04/216.04 (1/1) [MH+].
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].[I:18]I.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[I:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ncc2c1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
In a round-bottomed flask, 5-(tert-butyl-dimethyl-silanyloxy)-1H-indazole (1.20 g, 4.83 mmol) was dissolved in DMF (12 ml). Iodine (2.45 g, 9.66 mmol) was added followed by potassium carbonate (2.58 g, 18.7 mmol). The dark suspension was stirred at room temperature for 3 h then quenched with 10% aqueous NaHSO3 and extracted with diethyl ether (2×). The combined organic layers were washed with 10% aqueous NaHSO3, three times with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 1.65 g (91%) of 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1H-indazole as a dark brown foam.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].N1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(OCCOCC)C>>[N:4]1([S:1]([NH2:5])(=[O:3])=[O:2])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: NS(N)(=O)=O
Reactant: C1COCCN1
Agent: CCOCCOCC
Product: NS(=O)(=O)N1CCOCC1
Temperature: 120 °C
Reaction time: 11 h
Yield: 76.6 %

Procedure:
5.00 g of sulfamide, 4.09 g of morpholine and 5 ml of 1,2-diethoxyethane were mixed and heated with stirring in an oil bath at 120° C. for 11 hours. The reaction solution was air-cooled to room temperature and the crystal was washed with diethyl ether, washed with methanol and then dried under reduced pressure to obtain 5.98 g of the desired compound as an brownish crystal having a melting point of 158 to 161° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:12][N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (189 mg, 0.49 mmol), trimethylsilylacetylene (103 μL, 0.73 mmol), triphenylphosphine (4 mg, 0.02 mmol), and triethylamine (102 μL, 0.73 mmol) were stirred in THF (4 mL) in a flask purged with nitrogen. Dichlorobis(triphenylphosphine)palladium(I) (17 mg, 0.024 mmol) was added, and after 10 min copper iodide (2 mg) was added. The reaction stirred for 18 h at r.t. The solution was diluted with EtOAc, washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CHCl3) gave 168 mg (85%) of the title compound as a clear oil. MS (ES) [m+H] calc'd for C22H27N5OSi, 406; found 406.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](O)=[O:10])=[N:6][CH:7]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][OH:10])=[N:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Solvent: C1CCOC1
Product: OCCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 117.3 %

Procedure:
Commercially available 2-(5-bromopyridin-2-yl)acetic acid (1.00 g, 4.6 mmol) in tetrahydrofuran (10 mL) is cooled to 5° C. and treated dropwise over 10 minutes with borane-tetrahydrofuran complex (13.9 mL, 13.9 mmol). After stirring at room temperature for 4 hours, the reaction mixture is quenched with saturated aqueous potassium carbonate (20 mL), extracted with ethyl acetate (50 mL), dried over MgSO4, filtered, the solvent removed under reduced pressure, and the crude material purified by column chromatography on silica gel eluting with a gradient of neat heptane to neat ethyl acetate to afford the title compound (1.09 g): m/z (Cl) 203 [M+H].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:27]=[N:26]C=2C=1.NN>ClCCl>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:26][NH2:27])=[O:8]
Reactant: O=C(O)[C@H]1CCCO1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: ClCCl
Product: NNC(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 445.7 %

Procedure:
A mixture of (R)-tetrahydrofuran-2-carboxylic acid (5.00 g, 43.1 mmol, 1.00 equiv), EDCI (12.4 g, 64.6 mmol, 1.50 equiv) and HOBt (8.70 g, 64.4 mmol, 1.50 equiv) in dichloromethane (100 mL) was stirred for 30 min at 25° C. To the mixture was then added hydrazine (2.00 g, 62.4 mmol, 1.50 equiv) dropwise. The resulting mixture was stirred overnight at 25° C. The solids were removed by filtration, and the filtrate was concentrated in vacuo to furnish 25.0 g (crude) of (R)-tetrahydrofuran-2-carbohydrazide as a yellow oil.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([N+:13]([O-])=O)[C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24]>C(O)C.[Fe]>[F:10][C:9]1[C:4]([F:3])=[C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:6]([NH2:13])=[C:7]([O:11][CH3:12])[CH:8]=1
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Temperature: 25 °C
Yield: 89 %

Procedure:
Ammonium chloride (1.18 g, 20.16 mmol) and iron powder (1.15 g, 21.44 mmol) were added to a stirred solution of (2,3-difluoro-5-methoxy-6-nitro-phenyl)-(2-fluoro-4-iodo-phenyl)-amine (0.57 g, 1.34 mmol) in ethanol (20 mL). The mixture was stirred at reflux for 16 hours, cooled to room temperature, filtered over celite and the filtrate concentrated to dryness. The resulting residue was taken into ethyl acetate, washed with water, dried over sodium sulfate and further purified by crystallization from ethanol to provide the product as an off-white solid (0.47 g, 90.3%). M+H+: 393.2. 1H NMR (DMSO, 300 MHz): 3.76 (s, 3H); 6.1 (t, 1H); 6.8-7.0 (m, 1H); 7.2 (d, 1H); 7.35 (s, 1H); 7.42 (d, 1H).
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[C:15]([O:19][C:20]([NH:22][C@@:23]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][C:27](=[O:29])[C@@H:26]2[C@H:24]1[C@H:25]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+].OO>O1CCCC1>[C:15]([O:19][C:20]([NH:22][C@@:23]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][C@H:27]([OH:29])[C@@H:26]2[C@H:24]1[C@H:25]2[C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C([O-])O
Agent: OO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
Add 1M lithium tri(sec-butyl)borohydride in tetrahydrofuran (42.27 mL, 42.27 mmol) dropwise to di-tert-butyl (1S,2S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylate (7.10 g, 17.25 mmol, see WO03/104217/A2 for synthesis details) in tetrahydrofuran (431.35 mL) at 0° C. and stir. After 90 minutes, carefully add 1M aqueous sodium bicarbonate (60.07 mL, 62.11 mmol) followed by hydrogen peroxide (30% wt, 2.64 mL, 86.27 mmol) at 0° C. The reaction is warmed to room temperature. After 40 minutes, the reaction is extracted with ethyl acetate, washed with 10% aqueous citric acid followed by brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography eluting with 5-50% ethyl acetate in hexanes to give the title compound (6.70 g, 16.20 mmol, 94%).
Reaction SMILES: BrCC1CC1(F)F.[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][C:17]1[N:18]=[C:19]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:8]([N:29]1[CH2:30][CH2:31][N:27]([C:19]2[S:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH3:16])[N:18]=2)[C:28]1=[O:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC1(F)CC1CBr
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)nc1C
Yield: 93 %

Procedure:
Following the procedure as described in Preparation 13, making variations as required to replace bromomethyl-2,2-difluorocyclopropane with benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 93% yield: mp 122-124° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35-7.26 (m, 5H), 4.40 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.48 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); MS (ES+) m/z 346.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20]C(OCC2C=CC=CC=2)=O)[CH2:8][C@@H:7]1[CH2:31][CH3:32])=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH2:31][CH3:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1CC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N)C[C@@H]1CC
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
A one liter, four neck flask under nitrogen atmosphere was charged with cis4-benzyioxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (40.1 g, 89 mmol, 1.0 equiv), methanol (400 mL), and ammonium formate (14.0 g, 223 mmol, 2.5 equiv). 10% Pd/C, 50% waterwet (4.0 g) was added, and the slurry heated to 40° C. over 1 h. After 1.5 h, the mixture was cooled to room temperature and filtered through celite. The cake was washed 2×100 mL methanol. The filtrate was concentrated to approximately 75 mL, transferred to a separatory funnel, and diluted with 400 mL ethyl acetate. The mixture was washed 1×125 mL saturated aq. NaHCO3, 1×100 mL brine, and dried (Na2SO4). The mixture was filtered and the filtrate concentrated to a clear oil. The oil was crystallized from 100 mL n-heptane to give cis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester as a white crystalline solid (26.05 g, 93%): mp 61.5-63.50° C.; 1H NMR (CDCl3, 400 MHz) δ0.79 (t, 3H, J=7.5 Hz), 1.24 (m, 4H), 1.42 (m, 1H), 1.51 (br s, 2H), 1.62 (m, 1H), 2.46 (m, 1H), 3.73 (m, 1H) , 4.17 (m, 2H), 4.36 (m, 1H), 7.44 (m, 2H), 7.66 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ154.6, 139.3, 138.9, 126.3 (q, J=32 Hz), 125.7, 124.3 (q, J=271 Hz), 123.5, 119.8, 61.96, 54.16, 46.91, 41.50, 28.85, 14.38, 9.60; DEPT spectrum: quaternary carbons δ154.6, 139.3, 138.9, 126.3, 124.3; CH carbons δ125.7, 123.5, 119.8, 54.16, 46.91; CH2 carbons δ61.96, 41.50, 28.85; CH3 carbons δ14.38, 9.60; IR (drifts) 3350 (s), 3293 (m), 2972 (s), 1697 (vs); MS (ES+) m/z (rel. intensity) 358 (M+H+CH3CN+, 55), 317 (M+H+, 7), 300 (100); Anal. Calcd for C15H19N2O2F3: C, 56.96; H, 6.06; N, 8.86. Found: C, 56.86; H, 6.28; N, 8.82.
Reaction SMILES: [ClH:1].C[O:3][C:4](=[O:20])[CH2:5][CH2:6][NH:7][CH2:8][CH2:9][CH:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH2:11]1>Cl>[ClH:1].[O:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH:10]([CH2:9][CH2:8][NH:7][CH2:6][CH2:5][C:4]([OH:20])=[O:3])[CH2:11]1
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Agent: Cl
Product: O=C(O)CCNCCC1COc2ccccc2C1

Procedure:
The starting material can be prepared, for example, as follows: 3.0 g (0.01 mol) of 3-{N-[2-(chroman-3-yl)ethyl]amino}propionic acid methyl ester hydrochloride are heated at boiling point for 4 hours, with stirring, with 20 ml of 4N hydrochloric acid. The reaction mixture is then concentrated by evaporation under reduced pressure and the residue is stirred with acetone, yielding 3-{N-[2-(chroman-3-yl)ethyl]amino}propionic acid hydrochloride having a melting point of 186°-188°.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.C(N(CC)CC)C.[Cl:23][CH:24]([Cl:28])[C:25](Cl)=[O:26]>O>[C:1]1([CH:7]2[N:11]([C:25](=[O:26])[CH:24]([Cl:28])[Cl:23])[CH2:10][CH2:9][S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2NCCS2)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(C(Cl)Cl)N1CCSC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Five grams of 2-phenyl thiazolidine was dissolved in 50 ml. of acetone, 3.1 g. of triethylamine was added and the mixture stirred in a room temperature water bath, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes and then poured into water, extracted with methylene chloride, separated, dried over magnesium sulfate, and the solvent stripped under vacuum. There was obtained a yield of 7.3 g. of an oil, the title compound, ND30 32 1.5836.
Reaction SMILES: Cl[Sn]Cl.Cl.[N+:5]([C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH:9]=1)([O-])=O.[OH-].[Na+]>>[NH2:5][C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][S:14][C:10]=2[CH:9]=1
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Nc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of SnCl2 (1.5 g, 1.9 mmol) and 5 mL of con.HCl was added 6-nitrobenzothiazole (0.60 g, 3.4 mmol) in a portion and resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was basified with aqueous NaOH and extracted with EtOAc. Combined organic layers were dried over Na2SO4 and concentrated in vacuo, yielding an oil (0.47 g, 3.2 mmol, 96%) which was identified as the amine (>95%) and subjected to the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][NH:7][CH2:6]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[NH:4][C@H:5]1[C@@H:10]([CH3:11])[CH2:9][CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1
Reactant: COC(=O)N[C@@H]1CNCC[C@@H]1C
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N[C@@H]1CN(Cc2ccccc2)CC[C@@H]1C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
The reductive amination of cis-(4-methyl-piperidin-3-yl)-carbamic acid methyl ester was carried out by charging 3.9 grams (1 equiv., 22.6 mmol) to 2.07 ml benzaldehyde (0.9 equiv., 20.4 mmol), 9.6 grams sodium triacetoxyborohydride (2 equivs., 45.3 mmol) and 39 ml methylene chloride (10 volumes). The reaction was stirred at 20° C. and was allowed to exotherm to 30°-35° C. The reaction was complete by GCMS within 30 minutes. The reaction was quenched with 78 ml saturated sodium bicarbonate (20 volumes), extracted into 78 ml methylene chloride (20 volumes) and concentrated to a clear oil. (70% yield). 1H NMR: δ7.2-7.3 (5 H, m, aromatic protons), 5.50-5.48 (1 H, d, J=8.8 Hz), 3.77-3.75 (1 H, d, J=8.0 Hz), 3.63 (3 H, s), 3.45-3.38 (2 H, m), 2.77-2.74 (2 H, d, J=11.2 Hz), 2.14-2.01 (1 H, m), 1.94-1.89 (1 H, m), 1.57-1.55 (1 H, brs), 1.37-1.20 (2 H, m), 0.876 (3 H, d, J=9.2 Hz).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[F:16].[CH3:17][S:18]SC.Cl>O1CCCC1>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([S:18][CH3:17])[C:8]=1[F:16]
Reactant: CSSC
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1c(C(=O)O)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Butyllithium (2.5M in hexane; 180 ml) was added dropwise with stirring to a cooled solution of 4-chloro-3-fluorobenzoic acid (37.5 g) in tetrahydrofuran at -40° C. for 3 hours. A solution of dimethyldisulphide (60.5 g) in tetrahydrofuran was added and the mixture was stirred at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were extracted with aqueous sodium hydroxide solution (2M). The aqueous layer was acidified to pill and extracted with ether, washed with water, dried (sodium sulphate) and filtered. The flitrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 4-chloro-3-fluoro-2-(methylsulphenyl)benzoic acid (32.84 8) as a yellow solid m.p. 149.5°-150.5° C.
Reaction SMILES: FC(F)(F)[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C1(CBr)CC1.C(OC(=O)C(SC1SC(N)=NC=1)C)C.C(OC(=O)CSC1SC(N)=NC=1)C.C1(CN2C3C(=CC=C(F)C=3)C(C(NC3SC=C(SCC(O)=O)N=3)=O)=C2)CC1>>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][CH:11]=2)[CH:7]=[CH:8]1
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Agent: BrCC1CC1
Agent: CCOC(=O)C(C)Sc1cnc(N)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: c1ccc2[nH]ccc2c1

Procedure:
6-trifluoromethylindole, R5X=cyclopropyl-methylbromide; NH2A=(2-amino-thiazole-5-ylsulfanyl)-propionic acid ethyl ester (prepared according to the procedure for the synthesis of (2-amino-thiazole-5-ylsulfanyl)-acetic acid ethyl ester described under the procedure for the synthesis of {2-[(1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (22.8 g), benzyl bromide (10.3 ml) and K2 CO3 (22.67 g) in DMF (200 ml) was stirred at rt for 72 h. The mixture was partitioned between diethyl ether and water, the organics separated washed with water, dried and evaporated under reduced pressure to give a white solid, 29.5 g.
Reaction SMILES: O.[OH-].[Li+].[Br:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([O:12]C)=[O:11].Cl>O.C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)COc1cccc(Br)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1cccc(Br)c1
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
At 0° C., lithium hydroxide monohydrate (8.41 g, 0.2 mol) is added to a solution of methyl 3-bromophenoxyacetate (19.66 g, 80 mmol) in solution in 100 ml of a water-THF mixture (3:1). Agitation is continued for 15 minutes at 0° C. and then the mixture is acidified by a 3N aqueous solution of hydrochloric acid. It is extracted with ether, dried over MgSO4, filtered and evaporated. 18.21 g of 3-bromophenoxyacetic acid is obtained (yield=98%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:27])[CH3:26])[CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[C:33]([OH:42])(=[O:41])[C@@H:34]([C@H:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35]>[Pd].C(O)C>[C:33]([OH:42])(=[O:41])[C@@H:34]([C@H:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35].[CH2:31]([O:30][C:28](=[O:29])[C:25]([CH3:27])([O:24][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)[CH:22]=[CH:21][C:20]=1[CH3:23])[CH3:26])[CH3:32]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Agent: [Pd]
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCNC2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
A 250 mL Parr bottle was charged with 0.27 g of 10% palladium on carbon (50% water) and covered with 20 mL ethanol. 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester (1.36 g, 3.09 mmol) was dissolved in 50 mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50 psi for 2 h. The catalyst was filtered through a celite plug. The filter cake was washed with 150 mL ethanol and the filtrated concentrated under reduced pressure. The resultant oil was taken up in 20 mL hot ethanol to which was added L-tartaric acid (464 mg, 3.09 mmol) in 10 mL hot ethanol. The solution was allowed to stir 24 h at ambient temperature. The white crystalline precipitate was collected by filtration to yield 805 mg (57%) of 2-methyl-2-(2-methyl-5-piperidin-3-yl-phenoxy)-propionic acid ethyl ester L-tartaric acid salt as a white crystalline solid.