Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[O:27][CH2:28][CH:29]=[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH2:38])=[O:37])[CH2:32][CH2:31]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[Cl:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Br>CN(C=O)C.O>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[O:27][CH2:28][CH:29]=[C:30]2[CH2:35][CH2:34][CH:33]([C:36]([NH:38][CH2:49][C:48]3[CH:51]=[CH:52][CH:53]=[C:46]([Cl:45])[CH:47]=3)=[O:37])[CH2:32][CH2:31]2)[N:22]=[CH:21]1
Reactant: NC(=O)C1CCC(=CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC1
Reactant: Clc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(Cl)c1)C1CCC(=CCOc2ccccc2-c2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 33.8 %

Procedure:
To a stirred solution of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethylidene)cyclohexanecarboxamide (177 mg, 0.320 mmol) in anhydrous DMF (3 mL) at 0° C. was added NaH (9.0 mg, 0.384 mmol). The resulting suspension was allowed to stir at room temperature for 45 min. To the resulting solution was added 3-chlorobenzyl bromide (79 mg, 0.384 mmol). After stirring overnight, the reaction mixture was carefully diluted with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was removed under reduced pressure and the crude product was taken to next step without further purification. To a solution of the crude ether was added acetic acid (1.0 mL) and MeOH (4.0 mL). The solution was stirred at 80° C. for 2 h. The solution was allowed to cool to room temperature and the pH was adjusted to ˜10 with 10% NaOH (aq). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layer were washed with water, brine, and dried. The solvent was removed in vacuo to afford the crude residue, which was purified by flash column chromatography on silica gel to afford the desired product (47 mg, 0.108 mmol, 34%). 1H NMR (DMSO-d6): 1.44-1.52 (m, 4H), 1.69-1.79 (m, 4H), 2.19-2.23 (m, 1H), 3.85 (s, 2H), 4.05-4.11 (m, 2H), 6.63 (d, 1H, J=10.5 Hz), 6.88-6.93 (m, 2H), 6.99 (t, 1H, J=6.8 Hz), 7.09-7.11 (m, 2H), 7.18 (d, 1H, J=7.6 Hz), 7.25 (t, 1H, J=7.6 Hz), 7.41-7.48 (m, 2H), 7.65 (s, 1H), 7.93 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH3:30]
Reactant: CCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 85.6 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroform ate in 40 ml of chloroform is added dropwise to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, a solution containing 5.2 g (0.088 mol) of propylamine in 80 ml of chloroform is added dropwise at -15° C. during 30 minutes, then the mixture is stirred for 1 hour below -10° C. Then the mixture is allowed to stand overnight under cooling by ice. For working up, the chloroform mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The chloroform phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.8 g (85.6%) of the named product in the form of yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([CH2:23][C@H:24]([NH2:31])[C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([CH2:23][C@H:24]([NH:31][C:17]([C:9]2[CH:8]=[CH:7][C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[C:11]([O:12][CH2:13][CH:14]3[CH2:15][CH2:16]3)[N:10]=2)=[O:19])[C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(C3CCCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (LC/MS): 411.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH2:7].Br[C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C=Cc1ccc(OC)c(OC)c1
Reactant: CCOC(=O)c1ccccc1Br
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1/C=C/c1ccc(OC)c(OC)c1

Procedure:
5 g (30.5 mmol) of 3,4-dimethoxystyrene were reacted with ethyl 2-bromobenzoate in dimethylformamide at 120° C. by the method of procedure 31a. 1.2 g (4%) [sic] of the product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([OH:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=2)[CH2:26][CH2:25]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)([OH:12])[C:9]([NH:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]3[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=3)[CH2:28][CH2:29]2)=[O:11])=[CH:14][CH:15]=1
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Reactant: O=C(O)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1cc(C2CCN(CCCNC(=O)C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(F)cc1F

Procedure:
Example 160 was prepared from bis(4-fluoro phenyl) (hydroxy)acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluoro phenyl}-2-methyl propanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 9.31 (s, br, 1 H), 8.44–8.33 (m, 1 H), 7.59–7.45 (m, 4 H), 7.39 (s, 1 H), 6.97 (t, 4 H, J=8.8 Hz), 6.80 (t, 1 H, J=9.6 Hz), 5.61–5.36 (br, 1 H), 3.57–3.43 (m, 2 H), 3.14–2.99 (m, 2 H), 2.99–2.84 (m, 1 H), 2.62–2.47 (m, 2 H), 2.47–2.29 (m, 1 H), 2.14–1.93 (m, 4 H), 1.81–1.59 (m, 4 H), 0.98 (apparent t, 6 H, J=6.8 Hz); ESMS m/e: 586.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[N:13]1[CH:18]=[CH:17][C:16]([NH:19][CH3:20])=[CH:15][CH:14]=1>>[CH3:12][C:4]1[N:3]=[C:2]([N:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CNc1ccncc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(N(C)c2ccncc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (0.178 g, 2.13 mmol) and (pyridin-4-yl)-methyl-amine (0.108 g, 1.84 mmol) by a procedure similar to examples 125c (0.224 g, 49%). 1H NMR (CDCl3): 8.39 (m, 2H), 7.91 (d, J=8.4, 1H), 7.73 (ddd, J=1.2, 6.6, 8.4, 1H), 7.41 (m, 1H), 7.23-7.29 (m, 1H), 6.79-6.82 (m, 2H), 3.70 (s, 3H), 2.83 (s, 3H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.C(OC([N:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][N:53]=2)[CH:48]=[C:47]1B(O)O)=O)(C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:47]1[NH:46][C:54]2=[N:53][CH:52]=[CH:51][CH:50]=[C:49]2[CH:48]=1)(=[O:20])=[O:21])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cc4cccnc4[nH]3)c2c1
Yield: 45.9 %

Procedure:
2-Methylsulfonyl-N-[3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl]benzenesulfonamide can be obtained as described in Example 47 from 157.7 mg of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 122 mg of 1-(tert-butoxycarbonyl)-7-azaindole-2-boronic acid, 7 ml of dimethylformamide, 500 μl of a saturated aqueous sodium hydrogencarbonate solution and 6.7 mg of tetrakis(triphenylphosphine)palladium[0]. 50 mg of 2-methylsulfonyl-N-[3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indazol-5-yl]benzenesulfonamide are thus obtained in the form of a creamy yellow solid which decomposes at approximately 200° C. (LC/MS analysis: Tr 2.88 minutes MH+=468).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:28]([O:30][CH3:31])=[O:29])(=[O:24])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:25]([S:22](=[O:23])(=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:26]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol) in DCM (2 mL) and pyridine (2 mL), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 350 mg of 3-[2-(benzo[b]thiophene-2-sulfonylamino)phenylsulfamoyl]-4-methoxybenzoic acid methyl ester. Tr 1.10 min, MS: 533.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 3.84 (s, 3H), 4.18 (s, 3H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 3H), 7.66 (s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 8.22 (dd, 1H), 8.34 (d, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:21])[CH:3]=1.N12CCCN=C1CCCCC2.[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:21])[CH:3]=1
Reactant: COC(=O)c1ccc(OC)c(-n2c(C)cc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 2 (1.6 g, 5.5 mmol) and N,N-dimethyl formamide (10 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6 mmol) was added followed by 2,4-difluorobenzyl bromide (0.77 mL, 6 mmol). The reaction mixture was stirred at 60 C for 4 h, was poured into saturated aqueous NaHCO3 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give the title compound as an orange foam (2.13 g, 93%), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J=2.64 and 11.6 Hz, 1H), 7.82 (td, J=2.7 and 6.8 Hz, 1H), 7.57 (m, 1H), 7.29 (d, J=11.6 Hz, 1H), 7.02 (m, 2H), 6.16 (m, 1H), 6.03 (d, J=3.5 Hz, 1H), 5.14 (s, 2H), 3.89 (s, 6H), 1.93 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.43 (1F), −116.04 (1F) ppm. ES-HRMS m/z 416.1310 (M+H calcd for C22H20F2NO5 requires 416.1304).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[S:13]1[C:17]2=[CH:18][N:19]=[CH:20][CH:21]=[C:16]2[CH:15]=[CH:14]1.[Br:22][C:23]1[CH:24]=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[Br:22][C:23]1[C:24]([C:14]2[S:13][C:17]3=[CH:18][N:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[N:25][C:26]([Cl:29])=[N:27][CH:28]=1
Reactant: Clc1ncc(Br)cn1
Reactant: c1cc2ccsc2cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1ncc(Br)c(-c2cc3ccncc3s2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.02 mL, 7.27 mmol) was added to a flask containing anhydrous THF (10 mL) and the mixture, while kept under an atmosphere of nitrogen, was cooled to −78° C. n-BuLi (2.5 M in hexanes, 2.9 mL, 7.27 mmol) was added dropwise to the mixture, which was stirred for 30 min. Thieno[2,3-c]pyridine (0.82 g, 6.06 mmol) dissolved in anhydrous THF (10 mL) was added to the reaction mixture dropwise. The reaction was stirred at −78° C. for 10 min and then at −40° C. for 20 min. 5-Bromo-2-chloropyrimidine, dissolved in anhydrous THF (5 mL) was added to the reaction slowly. The mixture was allowed to stir at −40° C. for 2 h and then was quenched with a 1:1 mixture of acetic acid/methanol (5 mL). The mixture was stirred for 15 min and a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.72 g, 6.66 mmol) in 10 mL of THF was added. The reaction was stirred for an additional 15 min and then the cooling bath was removed. The mixture was stirred for 1 h and then cooled to 0° C. with an ice bath. 5 N sodium hydroxide (50 mL) was added to the reaction mixture, which was stirred for an additional 5 min. The reaction was then diluted with ethyl acetate (30 mL) and water (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by column chromatography using a gradient of 5 to 40% ethyl acetate in hexanes to obtain a light brown solid. Yield=0.5 g. MS (M+H)+ 326/328.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([C:9]#[C:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6].C(=O)([O-])[O-].[H][H]>C(OCC)(=O)C.C(O)C.[OH-].[OH-].[Pd+2]>[CH3:19][Si:2]([CH3:1])([CH2:9][CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:3][CH2:4][C:5]([F:6])([F:7])[F:8]
Reactant: C[Si](C)(C#CCOC1CCCCO1)CCC(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(CCCOC1CCCCO1)CCC(F)(F)F
Temperature: 25 °C

Procedure:
A suspension of compound 3 (5.00 g, 20.00 mmol) palladium hydroxide on charcoal (0.68 g, 0.21 mmol) in ethyl acetate and ethanol (100 ml, 9:1) and sodiumhydrohen carbonate (0.165 g, 1.96 mmol) were stirred at room temperature and a pressure of 100 pounds inch-2 under hydrogen for 24. The reaction mixture was filtered and the solvent removed in vacuo to yield a colorless oil. The crude product was purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1), Rf: 0.58] to yield a colorless oil.
Reaction SMILES: Cl[S:2]([C:5]1[C:9]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]=1)(=[O:4])=[O:3].[CH2:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])[CH3:28]>>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:10]2[C:9]3[C:5]([S:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([CH2:27][CH3:28])[CH:30]=4)(=[O:4])=[O:3])=[CH:6][S:7][C:8]=3[CH:13]=[CH:12][N:11]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3scc(S(=O)(=O)Cl)c23)CC1
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(NS(=O)(=O)c2csc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Yield: 76.5 %

Procedure:
Prepared from tert-butyl 4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate (90.0 mg, 0.215 mmol) and 3-ethylaniline (33.9 mg, 0.28 mmol) to give the title compound as an off-white solid (82.7 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 2.47 (q, J=7.7 Hz, 2H), 3.00-3.53 (m, 6H), 4.02-4.44 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 6.75 (s, 1H), 6.66 (d, J=8.0 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 7.67 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.39 (d, J=5.5 Hz, 1H), 9.80 (s, 1H). MS (ESI+) m/z 503.2 (M+H)+. HPLC 97%, RT: 3.93 min (5-99% MeCN over 3 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30](Cl)[N:29]=1)=[O:21]>>[CH3:18][NH:19][C:20]([C:22]1[S:23][CH:24]=[CH:25][C:26]=1[NH:27][C:28]1[C:33]([Cl:34])=[CH:32][N:31]=[C:30]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)[N:29]=1)=[O:21]
Reactant: CNC(=O)c1sccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: CCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 3-(2,5-Dichloro-pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methylamide to yield a light yellow solid (6.7%). LCMS: m/z=499.46 (M+H+), 1H NMR (400 MHz, CDCl3) δ8.28 (m, 1H), 8.09 (d, 1H, J=1.8 Hz), 7.74 (m, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 3.78 (m, 2H), 2.96 (s, 3H), 2.34 (m, 2H), 2.06 (m, 2H), 1.36 (m, 6H), 1.21 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[C:4]([NH2:17])[C:3]=1[NH2:18].[N:19]#[C:20]Br>CO>[CH3:1][C:2]1[C:3]2[NH:18][C:20]([NH2:19])=[N:17][C:4]=2[CH:5]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:7]=1
Reactant: N#CBr
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)c1N
Solvent: CO
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc2nc(N)[nH]c12
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (See Example 1.G) (500 mg, 2.015 mmol) and cyanic bromide (0.484 mL, 2.418 mmol) were added to a round bottom flask at room temperature, suspended in methanol (10.0 mL) and allowed to stir for 1.5 h. Volatiles were removed under reduced pressure followed by the addition of saturated sodium bicarbonate. The precipitate was collected via filtration, washed with ethyl acetate and dried under reduced pressure to afford the title compound (557 mg, 2.039 mmol, quant. yield). Compound was carried forward without further purification or characterization. MS (ESI) m/z 273.8 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([OH:7])=[O:6].Cl.[CH3:13]O>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Br)cc(I)c1
Agent: Cl
Solvent: CCOCC
Product: COC(=O)c1cc(Br)cc(I)c1
Temperature: 40 °C
Yield: 94 %

Procedure:
A mixture of 3-bromo-5-iodobenzoic acid (9.0 g) in methanol (40 mL) was treated with 1M HCl in diethyl ether (27.5 mL). The reaction was heated overnight at 40° C. The solvent was then removed in vacuo, and the residue dissolved in ethyl acetate. The organic solution was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to afford 8.8 g (94%) of methyl 3-bromo-5-iodobenzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:15]=O)=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7]2.O.[OH-].[Na+].Cl.[CH3:21][C:22]([CH3:24])=[O:23]>>[Cl:1][C:2]1[C:3]([CH:15]=[CH:21][C:22](=[O:23])[CH3:24])=[C:4]([CH3:14])[C:5]([CH3:13])=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])([CH3:12])[CH2:7]2
Reactant: CC(C)=O
Reactant: Cc1c(C)c2c(c(Cl)c1C=O)CC(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c2c(c1Cl)CC(C)(C)C2
Yield: 35 %

Procedure:
To a solution of 14.7 g of the 7-chloro-2,2,4,5-tetramethylindan-6-carboxaldehyde in 48 ml of absolute acetone was added 23 ml of water and 25 g of 2% NaOH. After refluxing for 20 hours the solution was acidified with 2N HCl extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 5.35 g of the title compound as yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:25]1[CH2:26][CH2:27][N:22]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:23][CH2:24]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(NCCI)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of 6.92 g of N-benzyloxycarbonyl-2-iodo-ethylamine, 4.00 g of 1-benzylpiperazine, 15.66 g of potassium carbonate and 40 ml of hexamethylphosphoramide (HMPA) was stirred at room temperature for overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:methanol=15:1) to give 5.63 g of N-benzyloxycarbonyl-2-(4-benzylpiperazin-1-yl)ethylamine (yield: 70%, oily product, IR: 3230, 2910, 1710 cm-).
Reaction SMILES: [C:1]([C@@H:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH3:4])#[N:2].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[O:24][C:25]1[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][CH:36]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]([C:6]([NH:5][C@H:3]([C:1]#[N:2])[CH3:4])=[O:12])=[CH:32][CH:33]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc(Oc2cccc(OCc3ccccc3)c2)cc1
Reactant: C[C@@H](C#N)NC(=O)OC(C)(C)C
Product: C[C@@H](C#N)NC(=O)c1ccc(Oc2cccc(OCc3ccccc3)c2)cc1
Yield: 38.5 %

Procedure:
General procedure D was used to deprotect 0.65 mmol of 4 and immediately coupled to 0.975 mmol of 40. After flash chromatography 0.96 g (0.25 mmol) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=8.8, 2H), 7.49-7.21 (m, 6H), 7.00 (d, J=8.7, 2H), 6.80 (d, J=8.3, 1H), 6.65 (d, J=12.0, 3H), 5.22-5.08 (m, 1H), 5.03 (s, 2H), 1.65 (d, J=7.2, 3H).