Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1>[Ni].C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Cc1ccnc(N)c1N
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of 2-amino-4-methyl-3-nitropyridine (919 mg, 6.0 mmol), ethanol (20 mL) and Raney Ni (about 200 mg) was shaken under H2 (30-40 psi) for 1 h, then filtered. The filtrate was evaporated to dryness, giving 740 mg (100%) of the diamine 56, mp 114°-5° C. 1H NMR (DMSO-d6), 1.997 (s, 3H), 4.359 (s, 2H), 5.250 (s, 2H), 6.264 (d, 1H, J=3), 7.173 (d, 1H, J=3).
Reaction SMILES: [Br:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:40])=[C:10]([CH3:39])[C:11]=2[C:12]([C:14]2[CH:33]=[CH:32][C:17]([O:18][S:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=3)(=[O:21])=[O:20])=[C:16]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.[I-].[Mg+2].[I-].[C:46](OC(=O)C)(=[O:48])[CH3:47]>CCOCC>[C:46]([O:31][C:24]1[CH:23]=[C:22]([S:19]([O:18][C:17]2[CH:32]=[CH:33][C:14]([C:12]([C:11]3[C:10]([CH3:39])=[C:9]([CH3:40])[S:8][C:7]=3[CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:42][CH:41]=3)=[O:13])=[CH:15][C:16]=2[CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)(=[O:21])=[O:20])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])(=[O:48])[CH3:47]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C3CCCC3)c2)c1C
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2ccc(C(=O)c3c(Cc4ccc(Br)cc4)sc(C)c3C)cc2C2CCCC2)ccc1C(=O)O
Yield: 57 %

Procedure:
The tide compound was prepared according to the procedure in Example 22 using 4-{4-[2-(4-bromo-benzyl)-4,5-dimethyl-thiophene-3-carbonyl]-2-cyclopentyl-phenoxysulfonyl}-2-hydroxy-benzoic acid (0.211 g, 0.315 mmol), magnesium iodide (0.0876 g, 0.315 mmol) and acetic anhydride (2.5 mL) in ether. Purification on 2% H3PO4/MeOH treated silica gel, eluting with a 10 & 20% EtOAc/pet ether step gradient followed by crystallization from acetone/hexane gave 0.185 g (57%) of the tide compound as a white solid, mp 113-114° C. 1H NMR (DMSO-d6) δ1.27-1.34 (m, 2H), 1.51-1.58 (m, 2H), 1.63-1.78 (m, 4H), 1.80 (s, 3H), 2.25 (s, 3H), H), 2.95 (quintet, 1H), 3.86 (s, 2H), 6.97 (d, 2H), 7.24 (d, 1H), 7.38 (d, 2H) 7.52 (dd, 1H), 7.57 (d, 1H), 7.86 (d, 1H), 7.92 (dd, 1H), 8.16 (d, 1H) 13.8 (br s, 1H). mass spectrum (−ESI) m/z 709 (M−H). Anal. Calcd. for C34H31BrO8S2: C, 57.38; H, 4.39; N, 0.00. Found: C, 56.99; H, 4.38; N, 0.02.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>C(O)C>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[C:2](/[N:1]=[CH:20]/[N:21]([CH3:23])[CH3:22])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Yield: 98.8 %

Procedure:
A mixture of methyl 3-amino-5-(4-chlorophenyl)-2-thiophenecarboxylate (37.3 mmol, 10.0 g) and N,N-dimethylformamide dimethyl acetal (74.7 mmol, 8.9 g) in ethanol (350 mL) was heated at reflux for 3 hours. The solvent was removed by rotary evaporation. To the residue 15 mL of toluene was added and the solvent was removed by rotary evaporation. This was repeated three times. To the resulting sticky residue, 20 mL hexanes was added followed by the gradual addition of ethyl acetate at 0° C. until it solidified. The resulting solid was collected by filtration giving the product (11.9 g, 98.9%). 1H NMR (CDCl3): δ 3.08 (6H, d, J=6.5 Hz), 3.81 (3H, s),6.98 (1 H. s), 7.35 (2H, d, J=8.6 Hz), 7.53 (2H, d, J=8.5 Hz), 7.69 (1H, s). LCMS m/z=323 (m+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([C:17](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](C=O)=[CH:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:37]3[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:35]([CH3:34])[CH:36]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3cn(C)c4ccccc34)C1)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
TEA (0.14 ml, 1.0 mmol) was added to suspension of Intermediate 2 (290 mg, 0.86 mmol) in DCM (10 ml). The mixture was stirred at RT for 10 min and then the pH value was adjusted to 5 with AcOH. The mixture was treated with N-methyl-indol-3-carbaldehyde (164 mg, 1.03 mmol) and NaBH(OAc)3 (219 mg, 1.03 mmol) following the procedure described in Example 31, A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (380 mg) as a light orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]2[CH2:19][CH2:18][CH2:17][CH:13]2[C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCCN1c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (9 g, 40 mmol), L-proline (4.6 g, 40 mmol), and potassium carbonate (7 g, 50 mmol) in ethanol (50 ml) and water (40 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 6 with 1N aqueous HCl solution. The mixture was extracted with EtOAc (2×100 mL), the combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated to afford N-(5-bromo-2-nitro-phenyl)-pyrrolidine-2-carboxylic acid (6 g, 48%) which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1>O1CCCC1.O>[CH3:3][O:4][C:6]1[N:7]=[C:8]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH:27]2[C:32](=[O:41])[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[CH:35]=2)[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: COc1ccc(-c2ccc3nc(Cl)nc(N4CCNCC4C(=O)Nc4cccc(C)c4)c3n2)cc1OC
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(N2CCNCC2C(=O)Nc2cccc(C)c2)c2nc(-c3ccc(OC)c(OC)c3)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.5 %

Procedure:
24 mg (0.6 mmole) of 60% by weight NaH in mineral oil was suspended in dry tetrahydrofuran (3 ml) under a N2 atmosphere followed by the addition of methanol (0.4 mmole). The mixture was stirred at room temperature for 15 minutes, and 2-chloro-4-[(N-3-methyl-phenylcarbamoyl)-piperazin-1-yl]-6-(3,4-dimethoxy phenyl)-pyrido[3,2-d]pyrimidine (104 mg, 0.2 mmole) was added. The solution was heated at reflux under N2 for 1 hour and diluted with water. The crude product was extracted from the reaction mixture with ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and evaporated to dryness under reduced pressure. Preparative thin layer chromatography on silica, using a n-hexane/ethyl acetate mixture in a ratio of 1:5 as eluent, afforded the pure title compound (52 mg, yield 51%) which was characterized by its mass spectrum as follows: MS (m/z): 515 ([M+H]+, 100).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[N:6]=1.C([O-])([O-])=[O:14].[K+].[K+]>O1CCOCC1.O>[Cl:11][C:9]1[CH:10]=[C:5]2[NH:4][CH2:3][CH2:2][N:6]2[C:7](=[O:14])[N:8]=1
Reactant: Clc1cc(NCCBr)nc(Cl)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1nc(Cl)cc2n1CCN2
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of N-(2-bromoethyl)-2,6-dichloropyrimidin-4-amine (10 g, 18 mmol) in 1,4-dioxane (30 mL) and water (30.0 mL) was added K2CO3 (4.85 g, 35.1 mmol). The reaction mixture was stirred at 70° C. for 4 h, then directly used into next step without workup and purification.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].[I:18]I.[N+]([O-])(O)=O>C(Cl)(Cl)Cl>[C@@H:1]1([N:10]2[CH:17]=[C:16]([I:18])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3]
Reactant: II
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Solvent: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)cc1I
Yield: 61.8 %

Procedure:
A mixture of 15 (1.2 g, 4.9 mmol), iodine (1.50 g, 5.9 mmol), CHCl3 (6 mL), and 1 N HNO3 (24 mL) was heated at reflux for 2 hours, and then cooled. The crystalline solid was collected by filtration and washed with ether to give the title compound 16 as a white solid (1.12 g, 62%). 1H NMR (DMSO-d6) δ 11.6 (s, 1H, NH), 8.10 (s, 1H, H-6), 5.95 (d, 1H, H-1′), 5.52 (br, 1H, OH), 5.40-5.10 (br, 1H, OH), 4.15-3.90 (m, 2H, H-2′, H-3′), 3.80-3.60 (m, 3H, H-4′, H-5′), 3.60-3.30 (m, 1H, OH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:37])[CH2:35][CH3:36])[CH:28]=4)[CH2:23][CH2:22]3)=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 61 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 494.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17]CC1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCc1ccccc1OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1O)C(=O)OC(C)(C)C
Yield: 82.8 %

Procedure:
N-(2-(2-Benzyloxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester (4.66 g, 13.65 mmol) was dissolved in ethanol (35.6 ml) and was hydrogenated at room pressure in the presence of 10% palladium on activated carbon for 16 h. The reaction mixture was filtered through a plug of celite. The celite was washed with ethyl acetate (50 ml). The liquid phases were collected. The solvents were removed in vacuo. The crude product was purified by flash chromatography on silica (300 g), using ethyl acetatelheptane (1:2) as eluent, to give 2.84 g of N-(2-(2-hydroxyphenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:3]=1[CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[C:3]=1[CH2:13][N:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(Cl)cccc2N2CCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc(N2CCCC2)c1CN1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 132.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate (500 mg, 1.32 mmol, 1.00 equiv), dichloromethane (10 mL). The mixture was cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 490 mg (crude) of 1-[[2-chloro-6-(pyrrolidin-1-yl)phenyl]methyl]piperazine as yellow oil. LCMS (ESI, m/z): 280 [M+H]+.
Reaction SMILES: [CH:1]([Si:3]([CH:7]=[CH2:8])([CH:5]=[CH2:6])[Cl:4])=[CH2:2].[Cl:9][Si:10]([Cl:17])([Cl:16])[CH2:11][CH2:12][SiH:13]([Cl:15])[Cl:14]>>[Cl:14][Si:13]([Cl:15])([CH2:12][CH2:11][Si:10]([Cl:17])([Cl:16])[Cl:9])[CH2:2][CH2:1][Si:3]([CH2:7][CH2:8][Si:13]([Cl:15])([Cl:14])[CH2:12][CH2:11][Si:10]([Cl:17])([Cl:16])[Cl:9])([CH2:5][CH2:6][Si:13]([Cl:15])([Cl:14])[CH2:12][CH2:11][Si:10]([Cl:17])([Cl:16])[Cl:9])[Cl:4]
Reactant: Cl[SiH](Cl)CC[Si](Cl)(Cl)Cl
Reactant: C=C[Si](Cl)(C=C)C=C
Product: Cl[Si](Cl)(Cl)CC[Si](Cl)(Cl)CC[Si](Cl)(CC[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl)CC[Si](Cl)(Cl)CC[Si](Cl)(Cl)Cl
Temperature: 80 °C
Yield: 66 %

Procedure:
11.00 g (0.076 mol) trivinylchlorosilane was added to a 100 ml vessel followed by 2 ml 1,1,1,4,4-pentachloro-1,4-disilabutane. The solution was heated to 80° C. and 15 μL of a 10% H2PtCl6/IPA-solution was added. Strong exothermic reaction was observed and heat was switched off. Rest of 1,1,1,4,4-pentachloro-1,4-disilabutane was added slowly during 30 min keeping the temperature of the solution below 130° C. The total amount of 1,1,1,4,4-pentachloro-1,4-disilabutane was 61.50 g (0.234 mol, 2.6% excess). After addition heat was again switched on and solution was stirred for an hour at 110° C. After that solution was distilled yielding 47.08 g (66%) tris(3,3,6,6,6-pentachloro-3,6-disilahexyl)chlorosilane. B.p. 264° C./<0.5 mbar.
Reaction SMILES: Cl.C([C:9]1[S:13][C:12]([N+:14]([O-:16])=[O:15])=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]=1[CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])(OC(C)(C)C)=O>O1CCOCC1>[CH3:26][S:23]([NH:22][CH2:21][C:10]1[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:12]([N+:14]([O-:16])=[O:15])[S:13][CH:9]=1)(=[O:24])=[O:25]
Reactant: CC(C)(C)OC(=O)c1sc([N+](=O)[O-])c(S(N)(=O)=O)c1CNS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)NCc1csc([N+](=O)[O-])c1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
Hydrogen chloride (20 mL of a 4.0 M solution in 1,4-dioxane) was added to a solution of Boc-4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide (0.600 g, 1.44 mmol) in 1,4-dioxane (10 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. Purification of the residue by flash column chromatography (Teledyne Isco RediSep column; 60-100% ethyl acetate in hexanes) provided a yellow oil. This material was triturated with dichloromethane to afford a yellow solid that was collected by filtration to afford the desired product, 4-(methanesulfonylamino-methyl)-2-nitro-thiophene-3-sulfonic acid amide (0.400 g, 1.27 mmol, 88%). 1H NMR (400 MHz, DMSO-d6) δ: 2.96 (3H, s), 3.31 (2H, s), 4.35 (1H, d, J=5.4 Hz), 7.61 (1H, t, J=6.2 Hz), 7.85 (1H, s), 7.87 (2H, bs).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (73 mg, yield 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH2:9].C(N(CC)CC)C.Cl[O-].[Na+].[OH:20][N:21]=[CH:22][C:23]1[N:24]=[C:25]([CH:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:46])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:44])[F:43])=[N:37]3)[CH2:30][CH2:29]2)[S:26][CH:27]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:20][N:21]=[C:22]([C:23]2[N:24]=[C:25]([CH:28]3[CH2:29][CH2:30][N:31]([C:34](=[O:46])[CH2:35][N:36]4[C:40]([CH3:41])=[CH:39][C:38]([C:42]([F:45])([F:43])[F:44])=[N:37]4)[CH2:32][CH2:33]3)[S:26][CH:27]=2)[CH2:9]1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccccc1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4Cl)C3)cs2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-chloro-2-ethenylbenzene (0.035 g, 0.25 mmol), triethylamine (2.5 mg, 0.025 mmol) and Clorox® aqueous sodium hypochlorite solution (1 mL, 16.1 mmol) in dichloromethane (5 mL) was added 4-[4-[(hydroxyimino)methyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 2, Step C) (0.10 g, 0.25 mmol) in dichloromethane (5 mL) dropwise over 1 h at 0° C. The reaction mixture was allowed to stir for 1 h, then filtered through Celite® diatomaceous filter aid, and concentrated under reduced pressure to give an oil, which was purified by column chromatography on silica gel using 50% ethyl acetate in hexane as eluant to give 73 mg of the title compound as a white foam, melting at 115-122° C. (crystallized from methyl acetate/petroleum ether).
Reaction SMILES: [CH2:1]([NH:14][CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH3:21]>>[CH2:1]([NH:14][CH2:15][CH2:16][C:17]([NH2:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: N
Reactant: CCCCCCCCCCCCCNCCC(=O)OC
Product: CCCCCCCCCCCCCNCCC(N)=O
Reaction time: 168 h

Procedure:
A solution of methyl 3-(tridecylamino)propionate (0.77 g) in 10N-methanolic ammonia (7 ml) was allowed to stand at room temperature for 7 days. The resultant crystal was collected by filtration and washed with a small portion of methanol to give 3-(tridecylamino)propionamide (0.16 g).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1>C(=O)=O>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]=[C:8]=[N:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10]
Reactant: Cc1ccccc1N=C=O
Agent: O=C=O
Product: Cc1ccccc1N=C=Nc1ccccc1C
Yield: 85.8 %

Procedure:
133 g of o-tolylisocyanate and 5 g of solid, insoluble catalyst from Example 1a were heated together to 180° C. with stirring. After the evolution of 12.3 liters of carbon dioxide, which took place within 1.5 hours, the catalyst was suction filtered and the filtrate distilled. 95.3 g of di-o-tolyl-carbodiimide, b.p. 135°-137° C./0.1 Torr were obtained (87% of the theory).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15]>C1COCC1.O>[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:13]([CH3:12])[S:14]([CH3:17])(=[O:16])=[O:15])[N:7]=1)#[N:9]
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1nccc(C#N)n1)S(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a solution of 2-chloropyrimidine-4-carbonitrile (0.20 g, 1.43 mmol) in THF was 60% NaH (0.05 g, 2.00 mmol) in mineral oil. After 20 minutes, N-methylmethanesulfonamide (0.22 g, 2.00 mmol) was added. After 3 hours, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford N-(4-cyano-pyrimidin-2-yl)-N-methyl-methanesulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:20][CH:19]3[CH:15]([CH2:16][NH:17][CH2:18]3)[CH2:14]1)[CH:6]=[N:5]2.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28](O)=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([N:13]1[CH2:14][CH:15]3[CH2:16][N:17]([C:28]([C:27]4[CH:31]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=4[N:32]4[N:36]=[CH:35][CH:34]=[N:33]4)=[O:29])[CH2:18][CH:19]3[CH2:20]1)[CH:6]=[N:5]2
Reactant: COc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: Fc1cc2ncc(N3CC4CNCC4C3)nc2cc1F
Product: COc1ccc(-n2nccn2)c(C(=O)N2CC3CN(c4cnc5cc(F)c(F)cc5n4)CC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 44 and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C24H21F2N7O2, 477.2; m/z found 478.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.25 (s, 1H), 7.84 (t, J=7.6, 1H), 7.64 (dt, J=19.7, 10.8, 3H), 7.42 (dd, J=11.4, 8.0, 1H), 7.03 (dd, J=9.0, 2.8, 1H), 6.92 (d, J=2.8, 1H), 3.97-3.84 (m, 5H), 3.64 (dd, J=18.2, 14.6, 5H), 3.12 (dd, J=19.8, 8.6, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([OH:33])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14](=[O:34])[CH2:15][N:16]([CH2:30][C:31]([O:33][C:41]2[C:40]([F:43])=[C:39]([F:44])[C:38]([F:45])=[C:37]([F:46])[C:36]=2[F:35])=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)O)c2cccc(Oc3ccccc3)c2)C1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2cccc(Oc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [[2-((S)-3-tert-butoxycarbonylaminopyrrolidin-1-yl)-2-oxo-ethyl]-(3-phenoxyphenyl)amino]acetic acid 27 (4.36 g, 9.39 mmol) in DMF (30 mL) were added pentafluorophenol (1.88 g, 10.21 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (1.96 g, 10.22 mmol). The reaction mixture was stirred overnight at room temperature. It was then diluted with ethyl acetate, washed with 10% hydrochloric acid (×2), brine (×2), dried (Na2SO4) and concentrated in vacuo. The resultant solid was evaporated twice from diethyl ether to give the title compound as a colourless, glassy solid (3.4 g, 57%) which was used directly in the next step.