Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.NCC1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.NC1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>[OH-].[Na+]>[N:17]1[CH:18]=[CH:19][CH:20]=[C:10]([CH2:9][NH:8][C:6](=[O:7])[NH:3][CH2:2][C:1]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)[CH:16]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NCc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCc1ccc(C(=O)O)cc1)NCc1cccnc1
Yield: 92.9 %

Procedure:
N,N-carbonyldiimidazole (1.62 g, 10 mmol), 3-aminomethylpyridine (1.08 g, 10 mmol), p-aminobenzoic acid (1.52 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide solution are used according to the method for the production of compound III in Method two to obtain 2.65 g of 4-[(3-pyridylmethylureido)methyl]benzoic acid (intermediate M-38) as a white solid, with a yield of 93.3%. MS(ES+):m/e 286.13.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]([C:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.CN(C)C(=O)C>O>[C:11]1([NH:10][C:17]2([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:21][CH2:22]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)C1(Nc2ccccc2)CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 28.7 parts of (2-bromoethyl)benzene, 34.7 parts of ethyl 4-anilinoisonipecotate, 25 parts of N,N-diethylethanamine and 162 parts of N,N-dimethylacetamide is stirred for 2 h. 30 at 75°-80° C. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with 210 parts of 1,1'-oxybisethane. The combined extracts are washed twice with 200 parts of water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel using a mixture of trichloromethane and 2% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2,2'-oxybispropane, yielding ethyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 65° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:27][O:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].Cl>C1COCC1.O>[OH:24][CH:23]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:26][CH:25]=1)[CH:29]([O:28][CH3:27])[C:30]([O:32][CH3:33])=[O:31]
Reactant: COCC(=O)OC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Yield: 105.1 %

Procedure:
Sodium bis-(trimethylsilyl)amide (440 mL 0.44 mol 1.0 M in THF) was cooled to −70° C. under a nitrogen atmosphere. A solution of 4-benzyloxybenzaldehyde (85 g, 0.4 mol) and methyl methoxyacetate (52 g, 0.5 mol) in THF (0.5 L) was added dropwise at −70° C. over 2 hours, and the mixture was stirred for an hour. A solution of concentrated HCl (85 mL) and water (85 mL) was added at −70° C. The resulting solution was allowed to warm to ambient temperature and was extracted with MTBE (2×0.5 L). The combined extracts were washed with brine (0.5 L), dried (MgSO4), filtered, and concentrated under to give 133 g of a red oil.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:5]1[C:20]([F:21])=[CH:19][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][C:11]=2[F:18])=[C:7]([O:22][CH3:23])[CH:6]=1)[CH3:4].Cl.C(OCC)(=O)C.C[OH:32]>>[CH2:3]([C:5]1[C:20]([F:21])=[CH:19][C:8]([O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]([OH:32])=[O:1])=[CH:12][C:11]=2[F:18])=[C:7]([O:22][CH3:23])[CH:6]=1)[CH3:4]
Reactant: CO
Reactant: [OH-]
Reactant: CCc1cc(OC)c(Oc2ccc(C#N)cc2F)cc1F
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Temperature: 80 °C

Procedure:
An aqueous solution of NaOH 6N (70 mL, 420 mmol) was added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzonitrile (which may be prepared in accordance with the experimental described in Example 4, step 3; 4.0 g, 13.82 mmol) in methanol (140 mL). The reaction mixture was then stirred at reflux (80° C.) overnight. After cooling to 0° C., the reaction mixture was acidified by slow addition of concentrated HCl (25 mL) until pH=2. The mixture was then diluted by addition of ethyl acetate (300 mL) and the aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum to afford the title product as a beige solid (4.20 g, quantitative).
Reaction SMILES: C(Cl)(Cl)[Cl:2].Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:20][CH:19]=1)[C:11]#[N:12].[CH3:36][OH:37]>>[ClH:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])=[CH:22][CH:23]=1)[C:11](=[NH:12])[O:37][CH3:36]
Reactant: COc1cc(C#N)ccc1OCc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: ClC(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=N)c1ccc(OCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 25 ml of chloroform and 50 ml of anhydrous methanol saturated with anhydrous hydrogen chloride while cooling in ice, was added 4.8 g of 3-methoxy-4-(4 -phthalimidomethylbenzyloxy)benzonitrile. The mixture was stirred at room temperature for 24 hours, then concentrated, and admixed with ethyl acetate to yield 3.4 g of colorless or pink solid methyl 3-methoxy-4-(4-phthalimidomethylbenzyloxy)benzimidate hydrochloride; m.p. 221°-222° C.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CC1C=CC([OH:55])=CC=1>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([NH:12][CH:8]([CH2:7][C:1]4[CH:6]=[CH:5][C:4]([OH:55])=[CH:3][CH:2]=4)[C:9]([OH:11])=[O:10])=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: O=C(NC(Cc1ccc(O)cc1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 36 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Tyr Wang resin (125 mg, 0.8 mmol/g), producing 22 mg of the title compound (36% yield). MS: 610.22 (M−H+) HPLC Procedure A, retention time=16.14 min.
Reaction SMILES: [OH-:1].[Na+].BrBr.[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:7]=1[C:14](=[O:16])C.Br[O-].[Na+]>O.O1CCOCC1>[Cl:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]([Cl:13])[C:7]=1[C:14]([OH:16])=[O:1]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Agent: [O-]Br
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (−5° C.) solution of sodium hydroxide (252 g, 6.3 mol) in water (800 mL) was added bromine (86 mL, 1.68 mol) dropwise. The temperature of the reaction mixture was kept below −5° C. during the addition. A solution of 1-(2,6-Dichloro-3-fluorophenyl)ethanone (100 g, 480 mmol) in dioxane (800 ml) was added to the solution of sodium hypobromide in 1 h while maintaining the temperature below 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h. After the TLC showed absence of starting material, the excess sodium hypobromide was destroyed with sodium sulfite (100 g in 100 mL water). The resulting solution was heated to 90° C. for 2 h. The reaction mixture was acidified with conc. HCl with vigorous stirring. The acidic solution was concentrated to remove all the dioxane and then extracted with dichloromethane (2×500 mL). The organic layer was dried (Na2SO4) and concentrated to give an oily residue, which after trituration with hexanes gave the title compound as a white solid. 1H NMR (CDCl3, 300 MHz): δ=7.20 (dd, 1H, J=8.7, 8.4 Hz), 7.33 (dd, 1H, J=9.3, 4.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCOc1cccc(Br)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCOc1cccc(Br)c1
Temperature: 50 °C

Procedure:
Ethyl 4-(3-bromophenoxy)butanoate 6 from Example 5 was taken up in 100 mL THF and 50 mL water and treated with lithium hydroxide LiOH (hydrate, 4.9 g). The whole was heated at 50° C. for 2 days. The mixture was cooled to room temperature and acidified to pH 1 with 2N HCl. The aqueous was extracted with ethylacetate. The combined organics were washed with brine and dried over sodium sulfate to give crude 4-(3-Bromophenoxy)butanoic acid 7 as a sticky solid. 1H NMR (DMSO-d6, 500 MHz) 7.24 (m, 1H), 7.13 (m, 1H), 7.11 (m, 1H), 6.95 (m, 1H), 3.99 (m, 2H), 2.37 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([C:9]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1)=[O:8])=O.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].Cl>O1CCCC1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.ClCCl>[ClH:1].[CH:21]1([CH2:20][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[C:9]([C:7]3[O:8][C:3]([CH2:2][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[N:5][CH:6]=3)=[CH:10]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCNCC
Reactant: COc1cccc2c(C(=O)CNC(=O)CCl)cn(CC3CCCCC3)c12
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)Cc1ncc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)o1

Procedure:
To a solution of 2-chloro-N-[2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-2-oxoethyl]-acetamide (200 mg, 0.53 mmol) in tetrahydrofuran (2 ml) was added diethylamine (0.55 ml, 5.3 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was poured into a separating funnel and dichloromethane (30 ml) added. The organics were washed sequentially with 5% aqueous sodium carbonate and brine. The organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give a brown solid. The brown solid was dissolved in tetrahydrofuran (2 ml) and (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (505 mg, 2.12 mmol) added. The resulting reaction mixture was subjected to microwave irradiation at 150° C. for 15 minutes and quenched with methanol (20 ml). The solvent was removed in vacuo and the residue purified by flash chromatography using 50% (v/v) ethyl acetate in heptane, followed by semi-prep. HPLC [Method (ii)] to afford a white solid. The solid was dissolved in dichloromethane (˜5 ml) and hydrogen chloride (1M solution in diethyl ether; 1 ml) added. The mixture was concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt (77 mg, 0.2 mmol). 1H NMR (400 MHz, CD3OD) δH 0.97-1.12 (2H, m), 1.15-1.25 (3H, m), 1.44 (6H, t, J 6.9), 1.52-1.62 (2H, m), 1.62-1.77 (3H, m), 1.77-1.9 (1H, m), 3.36 (4H, q, J 6.7), 3.95 (3H, s), 4.26 (2H, d, J 7), 4.64 (2H, s), 6.77 (1H, d, J 8), 7.11 (1H, t, J 8), 7.38 (1H, s), 7.41 (1H, d, J 8), 7.56 (1H, s); EsIMS: m/z 396.1 [M+H]+, 323.4, 268.4.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[NH:15][C:7]3=[C:8]3[C:13]([C:12](=[O:14])[NH:11][CH:10]=[CH:9]3)=[C:4]2[CH:3]=1.CC(C)([O-])C.[K+].[CH3:34][Si:35]([CH2:38][CH2:39][O:40][CH2:41]Cl)([CH3:37])[CH3:36].C1[CH2:47][O:46][CH2:45][CH2:44]1>>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2=[C:6]3[N:17]=[C:16]([C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])[N:15]([CH2:47][O:46][CH2:45][CH2:44][Si:35]([CH3:37])([CH3:36])[CH3:34])[C:7]3=[C:8]3[C:13]([C:12](=[O:14])[N:11]([CH2:41][O:40][CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:10]=[CH:9]3)=[C:4]2[CH:3]=1
Reactant: C1CCOC1
Reactant: O=c1[nH]ccc2c3[nH]c(-c4c(F)cccc4Cl)nc3c3ccc(Br)cc3c12
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C[Si](C)(C)CCOCn1ccc2c(c1=O)c1cc(Br)ccc1c1nc(-c3c(F)cccc3Cl)n(COCC[Si](C)(C)C)c21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The intermediate from Example 1 Step E (1.76 g, 3.99 mmol) was suspended in 150 mL THF and the flask was immersed in a room temperature water bath followed by the addition 11 mL (2.7 equiv) of a 1M solution of potassium tert-butoxide (in THF). After 45 minutes, 1.79 g of SEMCl (2.7 equiv) was added. The reaction was allowed to warm to ambient temperature overnight. The volatiles were removed in vacuo and the crude residue was dissolved in EtOAc and washed sequentially with a saturated solution of NaHCO3 and brine. The solution was dried with MgSO4 and filtered. Evaporation of the solvent under reduced pressure provided the crude residue that was purified on silica gel (gradient elution from 0 to 30% EtOAc/hexanes).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)[N:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)CC1

Procedure:
3 g of 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-(4-fluoro-phenyl)-quinoline-3-carboxylic acid are refluxed in 30 ml of pyridine with 2.7 g of N-methylpiperazine for 6 hours. The solvent is distilled off in vacuo, the residue is taken up in 30 ml of water and the precipitate is filtered off cold with suction, washed with water, dried in vacuo over calcium chloride at 100° C. and recrystallized from glycol monomethyl ether.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10]Br>C(Cl)Cl>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][C:4]=1[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: BrBr
Solvent: ClCCl
Product: O=Cc1cc(O)ccc1Br
Reaction time: 22 h
Yield: 63.7 %

Procedure:
To a suspension of 3-hydroxybenzaldehyde (1 kg, 8.2 mol) in CH2Cl2 (10 L) was added a solution of bromine (1.3 kg, 8.2 mol) in CH2Cl2 (620 mL) over 1 h. After stirring for about 22 h, the solids were isolated by filtration, washed with CH2Cl2 (4 L), and dried under vacuum to afford of 2-bromo-5-hydroxybenzaldehyde as a tan solid (1.05 kg, 63%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7]/[CH:8]=[CH:9]\[Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]\[Sn:10]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reaction time: 3 h

Procedure:
Diethylamine (19 mL) was added to a solution of ((Z)-3-bromoprop-1-enyl)-tributyl-stannane (Intermediate 2, 7.52 g) in THF (60 mL) and the mixture was stirred for 3 hours. The reaction mixture was evaporated to dryness and the residue was purified by chromatography on a silica column which had been pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (4.75 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.C[Mg]I.[N-:12]=[C:13]=[O:14].[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:8][C:4]1[N:3]=[C:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[C:16]([CH3:17])[CH:15]=[CH:19][C:19]=2[O:18][CH3:17])=[O:14])[CH:7]=[N:6][CH:5]=1
Reactant: C1CCOC1
Reactant: Nc1cncc(Cl)n1
Reactant: [N-]=C=O
Agent: C[Mg]I
Product: COc1ccc(C)cc1NC(=O)Nc1cncc(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-amino-6-chloropyrazine (130 mg, 1 mmol) in 3 mL THF at 0° C. under nitrogen was added methyl magnesium iodide (3M in Et2O, 330 μL, 1 mmol) to give a yellow suspension that was stirred at 0° C. for 15 minutes. The suspension was treated with the isocyanate neat (147 μL, 1 mmol) and allowed to warm to room temperature overnight. The reaction was partitioned between EtOAc (30 mL) and 10% Na2CO3 (30 mL). The organics were isolated and washed 1×30 mL with 10% Na2CO3 and 1×30 mL with saturated NaCl. The organics were dried (MgSO4), filtered and concentrated to a crude residue that was triturated with EtOAc to give, after filtration, the urea product as a white solid (27 mg, 9%). 1H-NMR (400 MHz, CDCl3) δ8.26 (s, H), 8.23 (s, 1H), 8.17 (s, 1H), 8.09 (br s, 1H), 6.84 (d, 1H), 6.81 (d, 1H), 3.96 (s, 3H), 2.35 (s, 3H). LRMS (ESI, Positive) m/e 293.0 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH3:46])[CH:43]=[N:42][CH:41]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CC)cc2)CCN3CC(C)C)cc1
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-ethylimidazol-5-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (900 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (365 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-ethylimidazol-5-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (516 mg) (Compound 380) as yellow amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)=[O:5])C.S(=O)(=O)(O)O>CO>[CH3:1][O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:27])[CH:13]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[S:9][CH:10]=1)=[O:5]
Reactant: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Yield: 42 %

Procedure:
A solution of 2-[2-(4-chloro-phenyl)3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid ethyl ester (prepared in Example 31(B)(a), 105 mg, 0.25 mmol) in methanol (10 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 68 h. The reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μm, 60 Å, 25 cm×23 cm ID, 75/25 heptane/ethyl acetate) afforded 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole4-carboxylic acid methyl ester (41.3 mg, 40.7%) as a white solid: mp 156-157° C.; EI-HRMS m/e calcd for C19H21ClN2O3S (M+) 392.0961, found 392.0956.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18]O)(=[O:12])=[O:11].O=S(Cl)[Cl:22]>C(Cl)(Cl)Cl>[Cl:22][CH2:18][C:14]1[N:13]([S:10]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])(=[O:12])=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(C)c(S(=O)(=O)n2cccc2CO)c(C)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)(=O)n2cccc2CCl)c(C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of [1-(2,4,6-Trimethyl-benzenesulfonyl)-1H-pyrrol-2-yl]-methanol (1.4 g, 5.0 mmol) in CHCl3 (25 ml) was cooled with an ice bath. SOCl2 (1.1 ml, 15 mmol) was added slowly. The solution was allowed to warm to rt, and held an additional 45 min. The solution was then concentrated under reduced pressure. 2-Chloromethyl-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-pyrrole was obtained as a brown solid (1.5 g, 100%). 1H NMR (CDCl3) δ 7.28 (dd, 1H, J=3.3, 1.7 Hz), 6.98 (s, 2H), 6.38-6.34 (m, 1H), 6.19 (t, 1H, J=3.4 Hz), 4.58 (s, 2H), 2.50 (s, 6H), 2.30 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Br:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[C:44]([O:52][C:53]([F:56])([F:55])[F:54])[CH:43]=1>CCOC(C)=O.C(Cl)Cl>[Br:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH:7][CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([CH2:15][NH:16][C:17]3[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:13][CH2:14]2)(=[O:50])=[O:49])=[C:44]([O:52][C:53]([F:55])([F:54])[F:56])[CH:43]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester (3.84 g, 9.28 mmol) in EtOAc (50 mL) was added 4 M hydrogen chloride in EtOAc (38 mL). The mixture was stirred at ambient temperature for 40 min and concentrated to give a white solid. To a suspension of the solid in CH2Cl2 (50 mL) was added diisopropylethylamine (6.46 mL, 37.1 mmol). The mixture was cooled at 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (3.31 g, 9.75 mmol) in CH2Cl2 (10 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give trans-4-bromo-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide (3.45 g, 60%) as a pale yellow solid.