Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCC[O:4]C1C=CC([NH2:11])=CC=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1.O.O.Cl[Sn]Cl>C(O)C>[NH4+:11].[OH-:4].[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Agent: Cl[Sn]Cl
Agent: Nc1ccc(OCCCl)cc1
Solvent: CCO
Solvent: O
Product: [NH4+]
Product: [OH-]
Temperature: 70 °C

Procedure:
4-(2-Chloro-ethoxy)-phenylamine can be synthesized by the following procedure. A suspension of 1-(2-chloro-ethoxy)-4-nitro-benzene (1.5 mmol) (from Example 1c) and SnCl2.2H2O (5.9 mmol) in absolute ethanol (120 mL) is heated at 70° C. for 2 h. The solvent is removed under vacuum and the residue is dissolved in 5% NaOH and extracted with EtOAc (3×50 mL). The organic layer is washed with 5% NaOH (1×50 mL), water (1×50 mL), brine, and dried over Na2SO4 and reduced to dryness. The dark crude residue is purified by silica chromatography using a mixture of DCM:MeOH:NH4OH=9:1:0.1 to isolate 4-(2-chloro-ethoxy)-phenylamine (90%) which is converted in the hydrochloride salt by treatment with HCl (1 eq of a 4N solution in dioxane). 1HNMR (400 MHz, CD3OD) δ 7.35-7.33 (m, 2H), 7.16-7.05 (m, 2H), 4.38 (m, 2H), 3.87 (m, 2H). MS (m/z) (M+1)+173.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1)=[O:4].[Li+].[OH-].Cl>O1CCOCC1.C(OCC)(=O)C>[F:24][C:22]([F:23])([F:25])[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:13]2[C:9]3[S:10][CH:11]=[CH:12][C:8]=3[CH:7]=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2ccsc2c1OCc1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
323 mg 7-(4-Trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carboxylic acid methyl ester was dissolved in 10 ml of 1,4-dioxane. To this was added 4.4 ml of 1 M LiOH (aq), and the reaction was stirred for 7 h at 60° C. and overnight at room temperature. The reaction mixture was diluted with 5 ml of ethyl acetate, acidified to pH 3 with 2N HCl (aq) and extracted with 10 ml ethyl acetate 4 times. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo to give 271 mg of 7-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-6-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17]CC1C=CC=CC=1)[CH:10]=2)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CCOC(C)=O.CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:25]#[N:26])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([OH:17])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2cc(OCc3ccccc3)ccc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(C#N)c2cc(O)ccc2c1O

Procedure:
1-Cyano-4,7-dihydroxy-isoquinoline-3-carboxylic acid ethyl ester was prepared by heating a mixture of 175 mg (0.50 mmol) of 7-Benzyloxy-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (example 52h), 630 mg (10 mmol) of ammonium formate, and 40 mg of 10% Pd/C in 3 mL of 1:1 EtOAc and EtOH at reflux temperature for 40 min. The resultant mixture was cooled, filtered through a celite pad to remove solids, and concentrated to a crude solid. The solid was triturated with hot ethanol to give 56 mg of off-white solid upon drying; MS (ESI+): 259.3 e/z (M+1)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:34][C:35]([F:39])([F:38])[CH2:36][NH:37][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 2,2,2-trifluoroethylamine hydrochloride (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 72 mg of the title compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[N:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C)C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[CH:18]=[N:19][C:20]([C:23]([N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[O:24])=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1ncc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1ncc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrimidinecarboxylic acid (E177b) (130 mg, 0.37 mmol) was dissolved in dimethylformamide (4 ml), treated with 1,1′-carbonyldiimidazole (180 mg, 1.11 mmol) and left to stir under argon at room temperature for 5 hours. The mixture was treated with morpholine (0.19 ml, 2.22 mmol) and allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:1.5:95) to afford the title compound (E177). MS (ES+) m/e 409 [M+H]+.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1C(=O)CCC1.O>[F:30][C:20]([F:19])([F:29])[C:21]1[N:22]=[CH:23][C:24]([CH2:27][CH2:28][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[CH:25][CH:26]=1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccc(CCn2c3c(c4cccnc42)CN2CCCC2C3)cn1
Reaction time: 24 h

Procedure:
A solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.328 mmol) and powdered KOH (128.5 mg, 2.296 mmol) in NMP (2 mL) was stirred at RT for 10 min. 2-(Trifluoromethyl)-5-vinylpyridine (113.5 mg, 0.656 mmol) was added into the reaction mixture and stirring continued for 24 h at RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel flash chromatography to yield 11-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([N:15]=O)S(C1C=CC(C)=CC=1)(=O)=O.[Cl:17][C:18]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:19]=1[O:20][C:21]1[CH:22]=[CH:23][C:24]([N+:39]([O-:41])=[O:40])=[C:25]([CH:38]=1)[O:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[O:29][CH2:30][C:31](Cl)=[O:32]>CO.CCOCC.O1CCCC1>[N+:4](=[CH:3][C:31](=[O:32])[CH2:30][O:29][C:28]1[CH:34]=[CH:35][CH:36]=[CH:37][C:27]=1[O:26][C:25]1[CH:38]=[C:21]([O:20][C:19]2[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:18]=2[Cl:17])[CH:22]=[CH:23][C:24]=1[N+:39]([O-:41])=[O:40])=[N-:15]
Reactant: O=C(Cl)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=CC(=O)COc1ccccc1Oc1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 42 °C

Procedure:
A mixture of potassium hydroxide in methanol (20.0 mL of a 4M solution ) is heated to 42° C. and treated dropwise with a mixture of N-methyl-N-nitroso-p-toluenesulfonamide (4 g, 18.7 mmol) in ether (40 mL). The diazomethane is distilled over, condensed with a dry ice/acetone condenser and collected. The diazomethane/ether solution is stirred in an ice-bath, treated dropwise with a solution of {o-[5-(2,4-dichlorophenoxy)-2-nitrophenoxy]phenoxy}acetyl chloride (1.09 g, 2.32 mmol) in tetrahydrofuran, stirred for 30 minutes and concentrated in vacuo to give the title product as a yellow oil which is identified by NMR spectral analyses.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[O:34][CH3:33])=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)CN1CCc2c(cc(OC)c(OC)c2OC)C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzyl-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26](OC)=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21.[BH4-].[Li+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:26]=[O:27])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([O:24][CH3:25])=[N:17][C:18]([CH3:23])=[N:19][C:20]=3[O:21][CH3:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(OC)nc(C)nc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Temperature: 0 °C
Reaction time: 15 h
Yield: 75.5 %

Procedure:
To a stirred solution of methyl 9-chloro-1-(4,6-dimethoxy-2-methylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (627 mg, 1.50 mmol) in tetrahydrofuran (15 mL) was added lithium borohydride (131 mg, 6.00 mmol) at room temperature. After being stirred for 15 h at 0° C., the reaction mixture was quenched with aqueous ammonium chloride, extracted with ethyl acetate, and concentrated in vacuo. The resulting solid was washed with ethyl acetate and dissolved in dimethyl sulfoxide (15 mL). To the solution was added Dess-Martin reagent (1.27 g, 3.00 mmol) at room temperature, and the mixture was stirred for 15 h. The reaction mixture was diluted with ethyl acetate, quenched with aqueous sodium hydrogen carbonate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-80% ethyl acetate/hexane gradient mixture to give the title compound as a pale yellow solid (439 mg, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]([CH2:19][CH2:20][CH3:21])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCc1nc(Br)sc1C(=O)OCC
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OCC
Yield: 70.8 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (161 mg, 0.94 mmol), ethyl 2-bromo-4-n-propyl-1,3-thiazole-5-carboxylate obtained in Example (219a) (217 mg, 0.78 mmol) and diisopropylethylamine (0.27 mL, 1.56 mmol), to obtain 204 mg of the title compound as a white solid (71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH:28]1([NH:31][C:32]([C@@H:34]2[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]2)=[O:33])[CH2:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:28]1([NH:31][C:32]([C@@H:34]2[CH2:39][CH2:38][CH2:37][N:36]([C:24]([C:23]3[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=3/[CH:18]=[C:10]3\[C:11](=[O:17])[NH:12][C:13]4[C:9]\3=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:16]=[CH:15][CH:14]=4)=[O:25])[CH2:35]2)=[O:33])[CH2:30][CH2:29]1
Reactant: O=C(NC1CC1)[C@@H]1CCCNC1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N2CCC[C@@H](C(=O)NC3CC3)C2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Yield: 37.1 %

Procedure:
2-[4-(3-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (108 mg, 0.3 mmol) was coupled with (R)-piperidine-3-carboxylic acid cyclopropylamide (69.3 mg, 1.5 eq.), HOBt (40.5 mg, 1 eq.), EDC (86 mg, 1.5 eq.) and TEA (0.06 mL) in DMF (1 mL) to give 57 mg (37%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.[N:10]12[CH2:17][CH2:16][C:13]([C:18]([O:20]CC)=O)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2>C1COCC1>[N:10]12[CH2:11][CH2:12][C:13]([C:18]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=3)([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[OH:20])([CH2:14][CH2:15]1)[CH2:16][CH2:17]2
Reactant: CCOC(=O)C12CCN(CC1)CC2
Reactant: Fc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)(c1cccc(F)c1)C12CCN(CC1)CC2
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A solution of 3-fluorophenylmagnesiumbromide (1.0 M in THF, 3.3 mL, 3.3 mmol) was chilled down to 0° C. under Ar. Ethyl 1-azabicyclo[2.2.2]octane-4-carboxylate (0.1756 g, 0.958 mmol) in THF (4 mL) was slowly added to the reaction mixture at 0° C. over 20 min. The reaction was allowed to warm up to room temperature and then heated at 60° C. for 16 h. The reaction was chilled in an ice bath, quenched with saturated NH4Cl, and concentrated under vacuum. The resulting residue was treated with H2O and extracted with EtOAc. The combined organic layers were dried with MgSO4, filtered, and concentrated under vacuum to yield the desired product (0.242 g, 76.7%). EI-MS m/z 330 (M+H) Rt (1.45 min).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].C([N-]C(C)C)(C)C.[Li+].[N:25]1[N:26]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:43][CH3:44])[C:37](N(OC)C)=[O:38])=[CH:32][CH:31]=2)[N:27]=[CH:28][CH:29]=1>C1COCC1>[N:25]1[N:26]([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([O:43][CH3:44])[C:37]([C:12]3[O:11][C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)=[CH:14][CH:13]=3)=[O:38])=[CH:34][CH:35]=2)[N:27]=[CH:28][CH:29]=1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2nccn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-n4nccn4)cc3)o2)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.20 g, 0.71 mmol) in anhydr THF (10 mL) under argon in an oven-dried flask cooled to −78° C. was added lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene; 0.43 mL, 0.85 mmol) dropwise. After stirring for 1 hr at −78° C., a solution of 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.195 g, 0.71 mmol) in THF (2 mL) was added dropwise. After stirring for 25 min, the mixture was allowed to warm to room temp while stirring for 2 hrs. The reaction was quenched with the addition of saturated aqueous NH4Cl and EtOAc was added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (30% EtOAc-hexanes) provided 2-(4-(2H-1,2,3-triazol-2-yl)phenyl)-1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxyethanone as a yellow solid (0.07 g, 10% yield). MS: m/z 497.9 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=2)[C:13]([NH:15][C:16]2[S:17][C:18]3[CH2:45][CH2:44][CH2:43][CH2:42][C:19]=3[C:20]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)=[O:22])=[O:14])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1.[CH3:49][O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]([OH:57])=O.CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[CH:1]1([N:4]([CH2:9][C:10]2[CH:11]=[C:12]([CH:46]=[CH:47][CH:48]=2)[C:13]([NH:15][C:16]2[S:17][C:18]3[CH2:45][CH2:44][CH2:43][CH2:42][C:19]=3[C:20]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]3[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)=[O:22])=[O:14])[CH2:5][CH2:6][N:7]([CH3:8])[C:55](=[O:57])[CH2:54][O:53][CH2:52][CH2:51][O:50][CH3:49])[CH2:2][CH2:3]1
Reactant: COCCOCC(=O)O
Reactant: CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCC(=O)N(C)CCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1

Procedure:
A mixture of 194 mg of methyl 4-[2-(4-{[(2-{[3-({cyclopropyl[2-(methylamino)ethyl]amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 0.050 mL of (2-methoxyethoxy)acetic acid, 84 mg of WSC.hydrochloride, and 5.0 mL of DMF was stirred for 15 hours at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (5% methanol/chloroform), thereby obtaining 200 mg of methyl 4-[2-(4-{[(2-{[3-(11-cyclopropyl-8-methyl-7-oxo-2,5-dioxa-8,11-diazadodecan-12-yl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5][N:4]=[CH:3]1.S(Cl)([Cl:13])=O.C.[CH3:16][CH:17](O)[CH3:18]>>[ClH:13].[NH:4]1[CH2:5][CH:6]([C:8]([O:10][CH:17]([CH3:18])[CH3:16])=[O:9])[CH2:7][N:2]=[CH:3]1
Reactant: O=C(O)C1CN=CNC1
Reactant: CC(C)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: CC(C)OC(=O)C1CN=CNC1
Reaction time: 8 h
Yield: 84 %

Procedure:
1,4,5,6-Tetrahydropyrimidine-5-carboxylic acid hydrochloride (1.0 g, 6.08 mmol) was suspended in 2-propanol (50 ml) and thionyl chloride (0.76 g, 6.39 mmol) was added dropwise. The resulting mixture was refluxed 24 h. The pink solution was treated with charcoal and then reduced in volume to 15 ml by evaporating unreacted alcohol. By allowing the solution to stand overnight, white crystals (1.08 g, 84%) were obtained in three crops, mp 170° C. 300 MHz nmr confirmed product. Microanalysis calc.: C 46.49, H 7.26, N 13.56, found: C 46.49, H 7.25, N 13.64.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([S:20]([NH2:23])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:13]=[C:11]([NH:23][S:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:22])=[O:21])[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.9 %

Procedure:
3-(Tert-butoxycarbonylamino)propanoic acid (4 g, 21.2 mmol, 1.0 equiv) was dissolved in DCM (100 mL). Then phenylsulfonamide (15.1 mmol, 0.7 equiv), EDCI (3.45 g, 18.2 mmol, 0.85 equiv) and DMAP (0.37 g, 3 mmol, 0.15 equiv) were added to the mixture and stirred for 2 h at room temperature. The reaction mixture was cooled down to 0° C., ice water (100 mL) was added. The mixture was stirred for 15 min, separated and the water layer was extracted twice with dichloromethane. The combined organic layer was washed by 5% HCl, brine, dried over Na2SO4, concentrated to give tert-butyl 3-oxo-3-(phenylsulfonamido)propylcarbamate 5.3 g, gray oil, 100%. EDI-MS: 329.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ: 9.52˜9.43 (brs, 1H), 8.02˜7.96 (m, 2H), 7.61˜7.55 (m, 1H), 7.50-7.45 (m, 2H), 5.02˜4.93 (m, 1H), 3.30˜3.24 (m, 2H), 2.48˜2.41 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][OH:36])=[CH:4][N:3]=1.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(N(CC)CC)C.CC1C=CN=C(N)C=1C>ClCCl>[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([O:36][CH2:35][CH2:34]/[CH:33]=[CH:32]/[C:5]2[C:6]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]5[N:21]([CH3:29])[C:22]6[C:27]([CH:28]=5)=[CH:26][CH:25]=[CH:24][CH:23]=6)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=4)[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCO)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccnc(N)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(-c2csc3c(/C=C/CCOS(=O)(=O)c4ccc(C)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 28.7 %

Procedure:
A solution of N-(4-{4-amino-7-[(1E)-4-hydroxybut-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.20 g, 0.40 mmol) in dichloromethane (10 mL) was treated with p-toluene sulfonyl chloride (0.100 g, 0.521 mmol), triethyl amine (0.08 g, 0.80 mmol), and dimethyl amino pyridine (0.003 g, 0.02 mmol). The reaction mixture was stirred at room temperature for 24 hours. No workup was used. The compound was purified by flash chromatography on silica gel using 1:1 ethyl acetate: heptane then 100% ethyl acetate to give 0.075 g (29%) the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.70 (m, 1H), 8.60 (d, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.70 (d, 1H), 7.45 (m, 1H), 7.40 (m, 1H), 7.30 (m, 2H), 7.21 (m, 2H), 7.19 (m, 1H), 7.10 (m, 1H), 7.05 (m, 1H), 6.60-6.50 (d, 2H), 6.15-6.10 (m, 1H), 4.95 (s, 2H), 4.20 (t, 2H), 4.12 (s, 3H), 3.98 (s, 3H), 2.70 (q, 2H), 2.39 (s, 3H); LCMS (conditions a) Rt 4.28 min (95%), M+ 653.4.