Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:25]([NH:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:26]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1
Reaction time: 0.75 h
Yield: 102.5 %

Procedure:
To a solution of t-Butyl 4-amino-3-methoxyphenylacetate (0.123 g, 0.52 mmol) in methylene chloride (2.0 mL) was added phenyl isocyanate (60 μL, 0.55 mmol). The reaction was stirred for 45 min then concentrated to afford t-butyl 3-methoxy-4-phenylureidophenylacetate (0.190 g, 100%) as a pale yellow foam: 1H NMR (CDCl3, 300 MHz, ppm) 8.00 (d, 11 Hz, 1H) 7.65-6.94 (m, 7H), 6.80 (d, 9.0 Hz, 1H), 6.74 (s, 1H), 3.68 (s, 3H), 3.45 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: N(C1C=CC2OCCOC=2C=1)=C=S.[C:14]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1)(=[O:16])[CH3:15].CS[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[CH:31][N:30]=2>>[C:14]([N:17]1[CH2:18][CH2:19][CH:20]([CH2:23][NH:24][C:27]2[S:28][C:29]3[C:34]([N:35]=2)=[CH:33][CH:32]=[CH:31][N:30]=3)[CH2:21][CH2:22]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCC(CN)CC1
Reactant: CSc1nc2cccnc2s1
Agent: S=C=Nc1ccc2c(c1)OCCO2
Product: CC(=O)N1CCC(CNc2nc3cccnc3s2)CC1
Temperature: 140 °C
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-acetyl-4-piperidinemethanamine and 9 parts of 2-(methylthio)thiazolo[5,4-b]pyridine was stirred and heated for 20 hours at 140° C. The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13.5 parts (93%) of 1-acetyl-N-(thiazolo[5,4-b]-pyridin-2-yl)-4-piperidinemethanamine as a residue (intermediate 51).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:38].C(=O)([O-])[O-].[NH4+:43].[NH4+]>C(O)C>[ClH:38].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:8]([C:10]2[CH:30]=[CH:29][C:13]3[N:14]([CH3:28])[C:15]([CH2:17][N:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:43])[NH2:27])=[CH:22][CH:21]=4)[CH3:19])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C#N)cc1)n2C)c1cccnc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1cccnc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[O:23]>O1CCCC1.CCCCCC.O>[C:13]([NH:17][S:18]([CH2:21][CH:22]([OH:23])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:20])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=Cc1ccncc1
Reactant: CC(C)(C)NS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)CC(O)c1ccncc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (7.4 ml) in tetrahydro-furan (36 ml) was added dropwise a 1.6 M solution (30 ml) of 1-butyllithium in n-hexane under a nitrogen atmosphere at an inside temperature of from −62° C. to −48° C. over 5 minutes. After stirring for 30 min under ice-cooling, a solution of N-tert-butylmethane-sulfonamide (3.63 g) in tetrahydrofuran (15 ml) was added dropwise at an inside temperature of from −60° C. to −50° C. over 5 minutes. After stirring for 1 hr under ice-cooling, the mixture was cooled to an inner temperature of −60° C. again. 4-Formyl-pyridine (2.74 ml) was added dropwise and after stirring at room temperature for 5 hr, the mixture was left standing overnight. Water (250 ml) was gradually added to the reaction mixture under ice-cooling, and the mixture was extracted 4 times with ethyl acetate. The organic layers were combined and dried over magnesium sulfate and concentrated to dryness under reduced pressure to give N-tert-butyl-2-hydroxy-2-(4-pyridyl)ethane-sulfonamide (7.02 g) as a brown oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:20][C:18]1[CH:17]=[C:13]([CH:12]=[C:11]([Cl:10])[CH:19]=1)[C:14]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:16]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)cc(Cl)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.8 %

Procedure:
DIPEA (149.8 mg, 0.2 mL, 1.15 mmol) was added to a stirred solution of 3,5-dichloro-benzoic acid (49.2 mg, 0.25 mmol) in DMF (3 mL). HOBT (38.2 mg, 0.28 mmol) and EDCI (123 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 42 mg (32.8% yield) of biphenyl-4-carboxylic acid {2-[4-(3,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.36%. 1H NMR (DMSO-d6): δ 8.7-8.62 (t, 1H), 8.0-7.94 (d, 2H), 7.84-7.7 (m, 5H), 7.58-7.46 (m, 4H), 7.44-7.36 (m, 1H), 4.26-4.1 (bs, 2H), 3.74-3.46 (bs, 7H), 3.42-3.34 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[C:21]#[C:22][CH3:23])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:41])=[O:40])[CH2:17][C@@H:16]2[C:21]#[C:22][CH3:23])=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC#CC1CNCCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#C[C@H]1CN(S(=O)(=O)c2ccccc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,1,1,3,3,3-hexafluoro-2-(4-(2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol (155 mg, 0.423 mmol, Example 241, Step 3) and triethylamine (302 μL, 2.17 mmol, Sigma-Aldrich, St. Louis, Mo.) in DCM (3.2 mL) was added benzenesulfonyl chloride (63.5 μL, 0.504 mmol, Sigma-Aldrich, St. Louis, Mo.) drop-wise at 0° C. The solution was stirred for 30 min and then diluted with DCM and washed with water followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (0 to 50% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-4-(phenylsulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-2-propanol as a mixture of enantiomers.
Reaction SMILES: C(OC([N:8]1[CH2:33][CH2:32][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]5[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[CH2:12]1[C:11]2([CH2:10][CH2:9][NH:8][CH2:33][CH2:32]2)[CH2:14][N:13]1[C@H:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C#N)cn4)ccc31)C2
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)nc1
Reaction time: 3 h
Yield: 48 %

Procedure:
To a mixture of 2-[(R)-5-(5-cyano-pyridin-2-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (11-1a, 140 mg, 0.32 mmol) in dioxane (3 mL) was added 5 mL of 4N HCl in dioxane. The mixture was stirred for 3 hours. The volatiles were removed under reduced pressure to give the title compound as a brown solid (65 mg, 48%). MS (APCI) 345.1 (M+H)+. Retention time: 1.26 minutes XBridge C18 4.6×50 mm 5 um, 5-100% acetonitrile:water (0.1% formic acid).
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:16]([F:19])([F:18])[F:17])=[C:12]([CH2:14]O)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:21].C(=O)(O)[O-].[Na+]>ClCCl.O>[Br:21][CH2:14][C:12]1[CH:13]=[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:9]=[CH:10][C:11]=1[C:16]([F:19])([F:18])[F:17]
Reactant: BrP(Br)Br
Reactant: OCc1cc(Oc2ccccc2)ccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Oc2ccccc2)cc1CBr
Temperature: -5 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
[5-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol (0.493 g, 1.84 mmol) in dichloromethane (12 ml) under nitrogen was stirred and cooled to −5° C. A solution of phosphorus tribromide (173 μl, 1.84 mmol) in DCM (3.5 ml) was added dropwise over about 2 min. The solution was then allowed to warm to room temperature and left to stand overnight. The solution was cooled to 4° C. and stirred well as saturated aqueous sodium bicarbonate (11 ml) was added in portions over 2 min. The biphasic mixture was stirred for a further 20 min. The mixture was diluted with water and DCM. The phases were separated using a hydrophobic frit and the aqueous phase washed with DCM. The combined organic extracts were stored in a freezer over the weekend and the DCM solution decanted off from crystals of ice. The organic phase was further dried (MgSO4), filtered and the solvent removed in vacuo to leave crude 2-(bromomethyl)-4-(phenyloxy)-1-(trifluoromethyl)benzene as a colourless oil (0.425 g).
Reaction SMILES: [CH:1]1([CH:7]([NH:22][CH2:23][C:24]2[C:29]([N+:30]([O-])=O)=[CH:28][N:27]=[C:26]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:25]=2)[CH2:8][CH2:9][C:10]([N:12]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][CH2:14][OH:15])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:30][C:29]1[C:24]([CH2:23][NH:22][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9][C:10]([N:12]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:13][CH2:14][OH:15])=[O:11])=[CH:25][C:26]([O:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:27][CH:28]=1
Reactant: O=C(CCC(NCc1cc(Oc2ccccc2)ncc1[N+](=O)[O-])C1CCCCC1)N(CCO)C1CCCCC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc(Oc2ccccc2)cc1CNC(CCC(=O)N(CCO)C1CCCCC1)C1CCCCC1
Reaction time: 1 h

Procedure:
To a solution of 4,N-dicyclohexyl-N-(2-hydroxy-ethyl)-4-[(5-nitro-2-phenoxy-pyridin-4-ylmethyl)-amino]-butyramide (0.1 g, 0.18 mmol) in MeOH (10 mL) was added a catalytic amount of Pd—C (10% on activated carbon) under N2, and the reaction mixture was subjected to hydrogenation under 5 psi for one hour. The catalyst was filtered out, and the MeOH was evaporated to yield a residue which was purified by preparative TLC (100% EtOAc) to yield 4-[(5-amino-2-phenoxy-pyridin-4-ylmethyl)-amino]-4,N-dicyclohexyl-N-(2-hydroxy-ethyl)-butyramide as an oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>C(Cl)Cl>[CH3:10][S:11]([O:1][CH2:2][C@H:3]1[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[O:4]1)(=[O:13])=[O:12]
Reactant: OC[C@H]1CCC2(CC2)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (5R)-5-(hydroxymethyl)-4-oxaspiro[2.4]heptane (116 mg, 0.9 mmol) and Et3N-(183.8 mg, 1.82 mmol, Shantou Xilong chemical factory) in dry CH2Cl2 (6 mL) at −10° C. under N2, was added MsCl (203 mg, 1.4 mmol, Shanghai Haiqu chemical Ltd.) dropwise via a syringe. After stirring for 2 hrs at rt, the reaction was quenched with water ice (3 mL), and the water phases were extracted with CH2Cl2 (20 mL×2). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to give ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate as pale yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[CH3:11][C:12]1([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:23])([CH3:22])[CH2:14][CH2:13]1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15]([CH3:23])([CH3:22])[CH2:14][CH2:13][C:12]2([CH3:24])[CH3:11])=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
73.5 g (0.55 mole) of anhydrous aluminum chloride were added a little at a time, at 0°-5° C., to a solution of 70 g (0.55 mole) of 3-chloropropionyl chloride in 200 ml of methylene chloride, after which a solution of 94 g (0.5 mole) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 200 ml of methylene chloride was added dropwise at the same temperature. The mixture was stirred overnight at room temperature, poured onto 1 1 of ice/water and extracted with 3 times 300 ml of methylene chloride. The combined organic phases were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated down. 138 g of 6-(3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene remained as an oil. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH:20][C:28](=[O:30])[CH3:29])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: The mixture of 12.5 g of 4-(4-acetamidophenoxy)-3-nitro-5-sulfamoylbenzoic acid and 125 ml of acetic anhydride is refluxed for two hours under nitrogen and evaporated under reduced pressure. The residue is taken up in 125 ml of 2N aqueous sodium hydroxide and 25 ml of water, the solution washed with diethyl ether, filtered and the filtrate acidified with concentrated hydrochloric acid and the precipitate recrystallized from 33 and 50% aqueous ethanol, to yield the 4-(4-acetamidophenoxy)-3-nitro-5-acetylsulfamoylbenzoic acid decomposing at about 240°. The solution of 10.5 g thereof in 100 ml of water and 22 ml of 2N aqueous sodium hydroxide is hydrogenated over 2.5 g of 10% palladium on charcoal until the theoretical amount of hydrogen has been absorbed. The mixture is filtered, the filtrate acidified with concentrated hydrochloric acid and the precipitate recrystallized from aqueous ethanol, to yield the 4-(4-acetamidophenoxy)-3-amino-5-acetylsulfamoylbenzoic acid melting at 305°-306° with decomposition.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].C1COCC1.O.[Cl-].[NH4+]>[Fe].O>[CH2:12]([O:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:8])[CH3:13]
Reactant: CCOc1cc([N+](=O)[O-])ccc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(N)ccc1C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Fe powder (609 mg, 10.90 mmol) was added to a solution of ethyl 2-methyl-5-nitrophenyl ether (Intermediate 88, 395 mg) in a mixture THF/water (15 mL/5 mL) followed by ammonium chloride (583 mg, 10.90 mmol). The reaction mixture was stirred overnight under nitrogen. The reaction mixture was poured into water (20 mL) and the iron was filtrated. Ethyl acetate was used to wash the solid filtrated. The filtrate was extracted with ethyl acetate (3 times). The combined ethyl acetate layers were dried over sodium sulphate and concentrated to give the title compound (303 mg) which was directly used in the next step.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])=[N:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[Cl:12][C:11]([Cl:14])([Cl:13])[C:8]1[N:9]=[CH:10][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(Cl)(Cl)Cl)nc1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Product: CC(c1ccc(C(Cl)(Cl)Cl)nc1)S(C)=NC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a stirred solution of 5-[1-(methylthio)ethyl]-2-(trichloromethyl)-pyridine (B) (0.55 g, 2.3 mmol) and cyanamide (0.097 g, 2.3 mmol) in THF (7 mL) cooled to 0° C. was added iodobenzene diacetate (0.75 g, 2.3 mmol) in one portion. The resulting mixture was stirred at 0° C. for 1 hr and then at room temperature for 2 hr. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 50% acetone in hexane (v/v) to give 0.254 g of {1-[6-(trichloromethyl)pyridin-3-yl]ethyl}(methyl)-λ4-sulfanylidenecyanamide (3) as an off-white solid in 40% yield. 1H NMR for the diastereomeric mixture (300 MHz, d6-acetone) δ 8.87 (s, 1H), 8.21-8.25 (m, 2H), 4.65-4.76 (m, 1H), 2.86-2.66 (m, 3H), 1.88-1.92 (m, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[NH:11][C:12]([C:14]1[NH:18][C:17]2[C:19]([Cl:23])=[C:20]([Cl:22])[S:21][C:16]=2[CH:15]=1)=[O:13].CCN(CC)CC.[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34]>C(Cl)Cl>[Cl:22][C:20]1[S:21][C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@H:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]3[NH:1][C:33]([N:32]([CH3:36])[CH3:31])=[O:34])=[O:13])[NH:18][C:17]=2[C:19]=1[Cl:23]
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
To a solution of N-[(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 9, 240 mg, 0.5 mmol) and Et3N (101 mg, 1.0 mmol) in DCM (4 mL) was added a solution of dimethylcarbamoyl chloride (54 mg, 0.5 mmol) in DCM (1 mL). The reaction was stirred at ambient temperature for 2 hours, washed with saturated NaHCO3 (1 mL), water (1 mL), brine (1 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (50 mg, 23%) as a foam.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=O)[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14].CC(C)([O-])C.[K+].Cl.[Cl-].[Li+]>C1COCC1.[Cl-].[Na+].O>[CH:16]([O:15][C:13]([N:12]1[CH2:19][CH2:20][CH2:21][C:22](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[C:5]1=2)=[O:14])([CH3:17])[CH3:18]
Reactant: CCOC(=O)CCCN(C(=O)OC(C)C)c1c(C(=O)OC)ccc(Br)c1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)ccc2c1N(C(=O)OC(C)C)CCCC2=O
Temperature: 160 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Add a solution of 2-[(3-Ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-4-bromo-3-methyl-benzoic acid methyl ester (3.47 g, 7.81 mmol) in THF (120 mL) to a solution of potassium tert-butoxide (15.6 mL, 15.62 mmol, 1 M in THF) in THF (120 mL) at room temperature under an atmosphere of nitrogen. After 2 h, pour the mixture into ice/water. Treat aqueous phase with 1M HCl to pH neutral and extract with dichloromethane. Dry the organic layer over anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure. Dissolve the former crude in DMSO (66 mL) and add water (4 drops) followed by addition of lithium chloride (0.882 g, 20.8 mmol) and heat the resulting solution at 160° C. for 2 h. Cool the mixture to room temperature and pour into brine. Extract the mixture with ethyl acetate. Dry the organic layers over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (2.0 g, 72% over two steps): MS (ES+): 341 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](=O)[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]C([O-])(C)C.[K+]>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:16][C:15](=[CH2:18])[C:13]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(OCc3ccccc3)cc21
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1Cc2ccc(OCc3ccccc3)cc21
Temperature: 0 °C

Procedure:
H7.2 (13.0 g, 58.0 mmol) was dissolved in 300 mL THF. The resulting solution was cooled to 0° C. in an ice-water bath. Methyltriphenylphosphonium bromide (24.8 g, 69.6 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was added and some yellow solid appeared. Potassium 2-methylpropan-2-olate (69.6 mL, 69.6 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was then added dropwise over an hour. The reaction was stirred at 0° C. for another hour and then quenched by addition of 200 mL saturated NaHCO3. The THF solvent was evaporated by vacuum and the residue was extracted twice with 200 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and then concentrated in the presence of silica gel. The residue was purified by column chromatography with 10% EtOAc/hexane to afford H7.3 (4.1 g, 31.8%). MS ESI (pos.) m/e: 223.1 (M+H)+.