Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:23]=[C:24]([NH:28]C(=O)OC(C)(C)C)[S:25][C:26]=2[CH3:27])=[C:20]2[C:15]([N:16]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:17](=[O:38])[N:18]([CH3:37])[C:19]2=[O:36])=[N:14]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:28][C:24]1[S:25][C:26]([CH3:27])=[C:22]([C:21]2[N:13]([CH2:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[N:14]=[C:15]3[C:20]=2[C:19](=[O:36])[N:18]([CH3:37])[C:17](=[O:38])[N:16]3[CH2:39][CH:40]2[CH2:41][CH2:42]2)[N:23]=1
Reactant: Cc1sc(NC(=O)OC(C)(C)C)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1sc(N)nc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was synthesized by treating tert-butyl 4-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-methyl-1,3-thiazol-2-ylcarbamate with 10% TFA in dichloromethane at room temperature for 5 hours. Mass: 508.13 (M+H).
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>C(Cl)Cl.CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:10]([C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]2=[N:6][CH:7]=1)=[O:12])[CH3:20]
Reactant: O=C(O)c1cnc2occc2c1
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cnc2occc2c1
Reaction time: 0.5 h
Yield: 124.5 %

Procedure:
To a suspension of furo[2,3-b]pyridine-5-carboxylic acid (3.30 g, 20.2 mmol) in methylene chloride (80 mL), under a nitrogen atmosphere at room temperature, was added oxalyl chloride (4.2 mL, 48 mmol) and then four drops of dimethylformamide. The reaction mixture was stirred until gas evolution ceased (4-5 hours) and a clear solution resulted. This solution was evaporated in vacuo and the excess oxalyl chloride chased by evaporation with benzene. The residue was dissolved in chloroform (50 mL) and diethylamine (5.2 mL, 50 mmol) was added carefully. After 0.5 hours, the chloroform solution was washed with dilute hydrochloric acid, filtered through a pad of charcoal and evaporated to give crude product (5.49 g). This oil was distilled under vacuum to give purified product (3.62 g, 82% yield), bp: 168°-170° C./1.6 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>C(O)C.O>[CH2:17]([N:1]([CH2:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:4]=1)[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c(-c2ccccc2)sc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc(CN(Cc2ccccc2)c2c(-c3ccccc3)sc3ccccc23)cc1

Procedure:
Preparation of the starting material a solution of 15.0 g (67 mmol) of 3-amino-2-phenyl-benzo(b)thiophene and 7.8 g (74 mmol) of benzaldehyde freshly distilled in 50 milliliters of benzene is refluxed for 10 hours with a water trap. After cooling, it is diluted with benzene, the excess benzaldehyde is eliminated by stirring with a solution of sodium bisulphite, the organic phase is dried over Na2SO4 and evaporated: 3-benzylidenamino-2-phenyl-benzo(b)thiophene in the form of a crude oily product which crystallises when it is triturated with methanol: 19.0 g (91% of theory) of yellow crystals, mp 92°-93° C. (ethanol). 9.6 g (31 mmol) of this Schiff base and 12 g (0.32 mol) of NaBH4 in 300 milliliters of absolute ethanol are refluxed with stirring for 25 hours. The cooled reaction mixture is diluted in water and extracted with ether. By evaporating the organic phase dried over K2CO3, the 3-benzylamino-2-phenyl-benzo(b)thiophene is obtained in the form of a crude oily product which crystallises when it is triturated with methanol. 9.0 g (92% of theory), colourless crystals, mp 52°-53° C. (methanol).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11](N)=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.[OH-:15].[K+].Cl>CCO.O>[CH3:1][C:2]1[C:7]2[C:8]([C:11]([OH:15])=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(C)c2c(C(N)=O)nsc2c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(C(=O)O)nsc2c1
Temperature: 85 °C

Procedure:
To a solution of 4,6-dimethyl-benzo[d]isothiazole-3-carboxylic acid amide (20 mg, 0.097 mmol) in EtOH (10 mL) and H2O (2 mL) was added KOH (11 mg, 0.19 mmol). The solution was heated to 85° C. for 48 hours. The solution was cooled and was placed in an ice bath. Conc. HCl was added to adjust the pH of the solution to 2. The solid that precipitated out from the solution was collected by filtration. The white solid was dried and was confirmed to be the title compound (15 mg, 75%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([O:23][C:24](=[O:30])[CH:25](Br)[CH:26]([CH3:28])[CH3:27])[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:30])[CH:25]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:26]([CH3:28])[CH3:27])[CH3:22]
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Oc1cccc2c1cc(C)n2Cc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (20 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromoisovalerate (0.344 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (300 mL) and washed with H2O (4×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (10:1 Hexane:EtOAc) to afford a 1:1 mixture of 7: ethyl-2-bromoisovalerate. Further purification by column chromatography (10:1 Hexane:EtOAc) afforded 7 (0.09 g, 19%) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35].C(N(CC)CC)C>>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:22]2[CH2:21][CH2:20][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:24][CH2:23]2)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35]
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: Cc1nc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)cn1C

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride (22.8 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (11 mg, 23%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.O>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:12]=[CH:13]2
Reactant: O=S(=O)(c1ccc(Cl)cc1)n1ccc2cc(F)ccc21
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: O=S(=O)(c1ccc(N2CCNCC2)cc1)n1ccc2cc(F)ccc21
Yield: 48.9 %

Procedure:
A solution of 1-(4-Chlorobenzenesulfonyl)-5-fluoro-1H-indole (0.210 g, 0.7 mmole) and anhydrous piperazine (0.3 g, 3.4 mmole) in dimethylsulfoxide (3.0 mL) was heated at 100° in a sealed tube for 16 h. The reaction mixture was diluted with 15 mL water and extracted with 20 mL ethyl acetate. The organic phase was washed with three 10 mL portions of water, 10 mL saturated sodium chloride, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to provide the 5-Fluoro-1-(4-piperazin-1-yl-benzenesulfonyl)-1H-indole (0.123 g), m.p. 77–78°.
Reaction SMILES: [C:1]1([C@@H:7]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:20](Cl)(=[O:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)(=O)C>O1CCCC1>[C:23]1(/[CH:22]=[CH:21]/[C:20]([N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]([CH3:12])([CH3:13])[O:10][C:9]2=[O:14])=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC1(C)OC(=O)N[C@@H]1c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)N(C(=O)/C=C/c2ccccc2)[C@@H]1c1ccccc1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Reaction of the auxiliary (15) (0.300 g, 1.57 mmol) in solution in tetrahydrofuran (10 ml) at -78° C. with butyllithium (1.5M, 1.06 ml, 1.59 mmol) and cinnamoyl chloride (0.228 ml, 1.73 mmol) for 10 minutes and then at room temperature for 2 hours, with work-up and flash column chromatography using 20% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (26) as a solid (0.503 g, 99%) which was recrystallised from ethyl acetate/40-60 petroleum ether; mp 149° C.; νmax (CDCl3) 1682 and 1771 cm-1 ; [α]D26 (c 1 in CHCl3)=+26.0; (Found: C, 74.79; H, 5.94; N, 4.28. C20H19NO3 requires C, 74.75; H, 5.96; N, 4.36%); δH (CDCl3 ; 200 MHz) 1.04 (3H, s, C(CH3)2), 1.65 (3H, s, C(CH3)2), 5.24 (1H, s, CHPh), 7.20-7.64 (10H, m, ArCH), 7.80 (1H, d, J=15.8, CH=CHPh), 8.07 (1H, d, J=15.8, CH=CHPh); δC (125 MHz; CDCl3) 23.78 (CH3), 28.99 (CH3), 67.24 (CH), 82.47 (C), 117.17 (CH), 126.37 (CH), 128.48 (CH), 128.90 (CH), 130.70 (CH), 134.54 (C), 136.38 (C), 146.53 (CH), 153.33 (CO), 165.04 (CO); m/z (CI+, NH3) 322 (M+ +1)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.[NH2:20][C:21]1[C:30]2[C:25](=[C:26](Br)[C:27]([CH3:31])=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:33]([NH2:35])=[O:34]>>[NH2:20][C:21]1[C:30]2[C:25](=[C:26]([C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][N:15]=[CH:16]4)=[CH:11][CH:10]=3)[C:27]([CH3:31])=[CH:28][CH:29]=2)[N:24]=[N:23][C:22]=1[C:33]([NH2:35])=[O:34]
Reactant: CC1(C)OB(c2ccc3ccncc3c2)OC1(C)C
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2ccncc2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 2.30-2.36 (m, 3 H), 7.72-7.79 (m, 2 H), 7.94 (d, J=5.86 Hz, 1 H), 8.07-8.14 (m, 2 H), 8.22-8.31 (m, 1 H), 8.46-8.52 (m, 1 H), 9.29 (s, 1 H); ESI-MS m/z [M+H]+ 330.4.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=1)=[O:23])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide (191.8 mg) obtained in step 1 was dissolved in dimethylformamide (DMF, 1.5 ml), to which benzylbromide (0.07 ., 0.55 mmol) and potassium carbonate (K2CO3, 82.9 mg, 0.6 mmol) were added. The reaction mixture was stirred at room temperature for 4 hours. Dimethylformamide was distillated under reduced pressure, followed by extraction with ethylacetate (EtOAc). The extracted organic layer was dried over MgSO4, filtered and concentrated. The concentrated reactant was separated by column chromatography (developing solvent: hexane/ethylacetate=15/1) to give 220 mg of the target compound (yield: 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[N:35]=[C:34]([C:36]#[N:37])[CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CC#N>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([C:36]#[N:37])[N:35]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Reactant: N#Cc1cccc(CBr)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cccc(C#N)n2)C2CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC2)cc1
Yield: 77.9 %

Procedure:
Using General Procedure E, (R)-{3-[4-(4-methoxy-phenylamino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (0.681 g, 1.81 mmol), 6-bromomethyl-pyridine-2-carbonitrile (0.535 g, 2.71 mmol) and DIPEA (630 μL, 3.62 mmol) in CH3CN (20 mL) at 55° C. for 16 h gave the crude product as a pale brown oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:, 95:5, v/v) afforded (R)-(3-{4-[(6-cyano-pyridin-2-ylmethyl)-(4-methoxy-phenyl)-amino]-piperidin-1-yl}-butyl)-carbamic acid tert-butyl ester (0.696 g, 78%) as a yellow crystalline solid. 1H NMR (CDCl3) δ 0.95 (d, 3H, J=6.0 Hz), 1.40 (s+m, 11H), 1.65 (m, 4H), 1.86 (m, 2H), 2.13 (br t, 1H), 2.54 (br t, 1H), 2.73-2.86 (m, 3H), 3.06 (m, 1H), 3.31 (m, 1H), 3.54 (m, 1H), 3.73 (s, 3H), 4.50 (s, 2H), 6.06 (br s, 1H), 6.68 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz), 7.52 (d, 1H, J=6.0 Hz), 7.54 (d, 1H, J=6.0 Hz), 7.70 (t, 1H, J=6.0 Hz).
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[CH2:11][OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:11][OH:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCC1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Temperature: 20 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of sat aq. NaHCO3 (44 g, 0.53 mol), CH2Cl2 (400 mL) and pyrrolidin-2-yl-methanol (53 g, 0.53 mol) was added a solution of 4-bromo-benzenesulfonyl chloride (127 g, 0.50 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided (R)-(1-(4-bromophenylsulfonyl)pyrrolidin-2-yl)methanol (145 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.66-7.73 (m, 4H), 3.59-3.71 (m, 3H), 3.43-3.51 (m, 1H), 3.18-3.26 (m, 1H), 1.680-1.88 (m, 3H), 1.45-1.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:38]([CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:40])=[O:39])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of phenylmethanesulfonyl chloride (168 mg, 0.879 mmol). The reaction mixture was stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was then stirred at RT for 1 h before the addition of phenylmethanesulfonyl chloride (67.2 mg, 0.352 mmol). The reaction mixture was stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (10 mg). LCMS (A) m/z: 439 [M+1]+, Rt 1.31 min (basic).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]([F:38])([F:37])[CH2:35]N.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:35][C:34]([F:38])([F:37])[F:33])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCC(F)(F)F)C1
Yield: 39 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2,2,2-trifluoroethylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (70 mg, 39%). LCMS (method B): RT=4.00 min, M+H+=528.
Reaction SMILES: C([C@@H]1COC(=O)N1C([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17]1)=O)C1C=CC=CC=1.[OH-].[Li+].[C:37]([O:40]CC)(=[O:39])C.Cl>C1COCC1.O>[C:31]([O:30][C:28]([N:18]1[CH2:19][C@@H:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C@H:16]([C:37]([OH:40])=[O:39])[CH2:17]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1

Procedure:
To a mixed solution of the compound (17.0 g) obtained in step 4 in THF (60 mL) and water (15 mL) was added at 0° C. 4N lithium hydroxide (35.1 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added ethyl acetate, and the mixture was acidified with 2N hydrochloric acid. The organic layer was dried, and the solvent was evaporated under reduced pressure to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (7.35 g) as a white powder.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C>CN(C=O)C.CO.[Cu]I>[N:16]1[NH:17][N:18]=[C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:11]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cn[nH]n1
Temperature: 100 °C
Yield: 98 %

Procedure:
To a solution of N-Boc-propargyl amine (1.60 g, 10.3 mmol) in a mixture of DMF:MeOH (4:1, 10 mL) was added trimethylsilylazide (2.0 mL, 15.2 mmol) and CuI (95 mg, 0.50 mmol). The resulting mixture was heated to 100° C. for 16 h, whereupon it was concentrated in vacuo and purified via silica gel chromatography, affording the title compound (2.0 g, 99%) as a light yellow oil; LCMS: m/z=196.9 (M−1).
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: CN(C)CCCCN
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCCCN(C)C)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(4-dimethylamino-butyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N(1),N(1)-dimethyl-butane-1,4-diamine in an analogous manner to Example 1396. Product isolated as an orange solid (31 mg, 51%). m.p.=132-134° C.; LCMS (m/e) 566 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.35 (s, 1H), 8.68 (d, 1H, J=8.4 Hz), 8.51 (s, 1H), 8.09 (s, 1H), 7.54 (d, 1H, J=7.8 Hz), 7.47-7.38 (m, 1H), 7.36 (s, 1H), 7.30-7.22 (m, 1H), 7.13-6.93 (m, 3H), 3.56 (t, 2H, J=4.8 Hz), 3.51-3.42 (m, 2H), 3.39 (s, 3H), 2.98-2.85 (m, 4H), 2.82-2.67 (m, 6H), 2.35 (t, 2H, J=5.8 Hz), 2.21 (s, 6H), 1.81-1.71 (m, 2H), 1.71-1.61 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9](C(OC(C)(C)C)=O)[CH:8]=[C:7]2[C:18]1[N:27]=[CH:26][C:25]2[NH:24][CH2:23][CH:22]3[CH2:28][O:29][CH2:30][CH2:31][N:21]3[C:20]=2[N:19]=1.C(Cl)Cl.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:18]1[N:27]=[CH:26][C:25]2[NH:24][CH2:23][CH:22]3[CH2:28][O:29][CH2:30][CH2:31][N:21]3[C:20]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ncc3c(n2)N2CCOCC2CN3)c2cccc(Cl)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc2c(-c3ncc4c(n3)N3CCOCC3CN4)c[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A mixture of tert-butyl 7-chloro-3-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-1H-indole-1-carboxylate and CH2Cl2/TFA (1:1) was heated to 50° C. and stirred for 2 hours. The reaction mixture was subsequently concentrated in vacuo and the crude product purified by LC/MS using a gradient of 30-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a tan solid (20 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ 2.98-3.01 (m, 2H), 3.56-3.58 (m, 3H), 3.72-4.25 (m, 3H), 4.65-4.92 (m, 1H), 6.34-6.58 (br s, 1H), 7.12-7.59 (m, 3H), 8.12-8.52 (m, 2H), 12.27-12.56 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C17H16ClN5O, 342.10. found 342.3.