Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][CH2:9][CH2:8]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](Cl)=[O:24].O>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]([N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:7][CH2:8][CH2:9]2)=[O:24])[CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=C(Cl)C=Cc1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(C=Cc1cccc(Cl)c1)N1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyridine (25 ml) was added to a mixture of 3,4-dihydro-2H-1,4-benzoxazine (17.8 g) in DCM (200 ml). The mixture was cooled on an ice bath and poured out into a mixture of m-chloro-cinnamoyl chloride (33 g) in DCM (100 ml). The mixture was stirred at room temperature overnight. Water was added and the mixture was decanted. The organic layer was dried, filtered and the solvent was evaporated till dryness, to give a residue which was purified by column chromatography over silica gel (eluent: cyclohexane/ethyl acetate 80/20) and recrystallisation from ACN/diethyl ether, yielding 26g (65.8%) of 4-[3-(3-chlorophenyl)-1-oxo-2-propen-1-yl]-2,3-dihydro-4H-1,4-benzoxazine (interm. 51).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:33]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH2:35]2)=[CH:32][C:9]2[N:10]([CH3:31])[C:11]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:21][NH:22]C(OC(C)(C)C)=O)[C:15]=3[Cl:30])=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:33]([N:34]2[CH2:39][CH2:38][CH:37]([C:40]([F:43])([F:42])[F:41])[CH2:36][CH2:35]2)=[CH:32][C:9]2[N:10]([CH3:31])[C:11]([NH:13][C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([CH2:21][NH2:22])[C:15]=3[Cl:30])=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CNC(=O)OC(C)(C)C)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cc2nc(Nc3c(Cl)ccc(CN)c3Cl)n(C)c2cc1N1CCC(C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(tert.-butoxycarbonylamino)-methyl]-phenylamino}-6-[4-trifluoromethyl-piperidinyl]-1-methyl-1H-benzimidazole-5-carboxylic acid ethyl ester (6.95 g, 11 mmol) and 26 mL 4M HCl in dioxane is stirred overnight. Then the organic phase is concentrated and the crude sub-title compound is directly used in the next step.
Reaction SMILES: [CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2:11].C(O)(=O)C.OC[CH2:18][C-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[CH-]1C=CC=C1.[Fe+2].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2]>>[CH3:18][C-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[C-:19]1([CH3:18])[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:11]
Reactant: OCC[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CC(=O)O
Product: C[c-]1cccc1

Procedure:
acetic acid ferrocene; hydroxyethylferrocene; ferrocene;
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11]([CH:17](N3CCCC3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10][C:9]=2[CH:8]=1.[ClH:30].C(OCC)(=O)C>CO>[ClH:30].[CH3:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[S:15][C:14]2[C:13](=[O:16])[NH:12][C:11](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:10][C:9]=2[CH:8]=1
Reactant: Cc1[nH]ncc1-c1cc2nc(C(Cc3ccccc3)N3CCCC3)[nH]c(=O)c2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1[nH]ncc1-c1cc2nc(/C=C/c3ccccc3)[nH]c(=O)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of a crude product (5.0 mg) of tert-butyl 3-methyl-4-{4-oxo-2-[(E)-2-phenylethenyl]-3,4-dihydrothieno[3,2-d]pyrimidin-6-yl}-1H-pyrazole-1-carboxylate produced in Example 94, step B, in methanol (1.0 mL) was added 4M hydrochloric acid/ethyl acetate solution (0.50 mL). The reaction system was stirred at room temperature for 30 min, and the mixture was concentrated under reduced pressure. The residue was crystallized from methanol/ethyl acetate to give the title compound (1.7 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[CH3:21][NH2:22].[BH4-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH3:21])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Product: CNCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
4-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}benzaldehyde (3 g, 9.98 mmol) was mixed with a methylamine (1.549 g, 49.9 mmol) alcohol solution. The reaction mixture was stirred at 23° C. overnight. NaBH4 (1.132 g, 29.9 mmol) was added and stirred for additional 2 h. Purification via an ISCO system then provided the title compound as a yellow solid. LCMS: rt=2.53 min, [M+H+]=316.1
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>C1(C)C=CC=CC=1.CCCCCCC>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 66.7 %

Procedure:
A solution which contained 19.5 g R-(+)-thioctic acid and 0.5 g S-(-)-thioctic acid in a mixture of 24 ml toluene and 6 ml n-heptane was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 13.0 g thioctic acid were obtained in the novel modification as first crystallizate. The R-(+)-thioctic acid content was 94.5% with a melting range of 45 to 48° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:16]1([CH2:22][CH2:23][C:24]#[CH:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[Cl-].[NH4+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:11]1([NH:10][C:3]2[C:2]([C:25]#[C:24][CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:7][N:6]=[C:5]([C:8]#[N:9])[N:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C#CCCc1ccccc1
Reactant: N#Cc1ncc(Br)c(NC2CCCC2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: N#Cc1ncc(C#CCCc2ccccc2)c(NC2CCCC2)n1
Yield: 89.9 %

Procedure:
5-Bromo-4-cyclopentylamino-pyrimidine-2-carbonitrile (0.69 mmol), 4-phenyl-1-butyne (1.66 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.035 mmol), copper (I) iodide (0.07 mmol) and triethylamine (2.1 mmol) in D (5 ml) is stirred at 75° C. for 2.5 h. The reaction mixture is treated with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and evaporated down. The crude product is applied to a silica gel column chromatography, which is eluted with following solvents: n-hexane:AcOEt=12:1 (v/v) and n-hexane:AcOEt=10:1 (v/v). The solvent of the latter effluent is removed by evaporation and dried in vacuo to afford the title compound. yield 89.9%, Rf=0.65 (n-hexane:AcOEt=2:1). 1H-NMR (400 MHz, CDCl3) δ 1.26-1.33 (m, 2H), 1.64-1.71 (m, 4H), 2.05-2.09 (m, 3H), 2.79-2.86 (m, 2H), 2.94-3.00 (m, 2H), 4.30-4.38 (m, 2H), 5.36-5.34 (m, 1H), 7.35-7.21 (m, 5H), 8.10 (s, 1H),
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18](OCC)=[O:19].O>CC(C)=O>[C:1]1([C:7]2[NH:17][C:18](=[O:19])[O:10][C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(N)=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
Benzoin (31.8 g, 0.15 mol) and urethane (42.79 g, 0.45 mol) were heated to reflux for 3.0 hours. The hot mixture was poured into water (150 mL). Acetone (150 mL) was added and heat was applied until the mixture dissolved. The solution was cooled and filtered, producing a white solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[C:27]1([O:33][CH2:34][C:35](Cl)=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:35](=[O:36])[CH2:34][O:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)COc5ccccc5)c4)CC3)cccc2n1
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and (phenyloxy)acetyl chloride.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)([CH3:5])[CH2:3][OH:4].O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.C(OCC)(=O)C.O>[NH2:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])=[CH:14]2
Reactant: CC(C)(CO)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO)c1cc2cc(N)ccc2[nH]1
Temperature: 120 °C
Yield: 97.9 %

Procedure:
To a solution of 2-methyl-2-(5-nitro-1H-indol-2-yl)propan-1-ol (0.094 g, 0.40 mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.451 g, 2.0 mmol). The mixture was heated in the microwave at 120° C. for 1 h. The mixture was diluted with ethyl acetate and water before being quenched with saturated aqueous NaHCO3. The reaction mixture was filtered through a plug of celite using ethyl acetate. The organic layer was separated from the aqueous layer, dried over Na2SO4, filtered and evaporated under reduced pressure to give 2-(5-amino-1H-indol-2-yl)-2-methylpropan-1-ol (0.080 g, 98%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>C1(C)C=CC=CC=1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 100 °C
Yield: 89.28 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.51 g, 17.29 mmol, 1.0 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in toluene (70 mL) respectively and heated to 100° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, and the mixture was reacted for 4 h. White solid was obtained by filtration (6.50 g, yield: 89.28%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][N:23](C)[CH2:22]4)=[O:17])[C:7]=2[CH:29]=1)#[N:2]>C(O)(=O)C.C(Cl)(Cl)Cl.[Zn]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[CH2:24][NH:23][CH2:22]4)=[O:17])[C:7]=2[CH:29]=1)#[N:2]
Reactant: CN1Cc2ccc(NC(=O)N[C@@H]3c4cc(C#N)ccc4OC(C)(C)[C@H]3O)cc2C1
Agent: [Zn]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2ccc3c(c2)CNC3)[C@@H]1O
Temperature: 80 °C
Yield: 29.4 %

Procedure:
A solution of (3S-trans)-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)-N'-(2,3-dihydro-2-methyl-1H-isoindol-5-yl)urea (1.0 g, 1.8 mmol, compound of example 19) in acetic acid (4 mL) was treated with zinc dust (0.35 g, 5.4 mmol) under argon and heated at 80° C. for 16 hours. Additional amount (0.4 g) of zinc dust was added and the reaction mixture was heated for eight hours. It was cooled to room temperature, diluted with chloroform (100 mL) and filtered. The solvent was evaporated in vacuo and the residue was acidified with 10% hydrochloric acid (10 mL). It was then extracted with ethyl acetate and the organic extract was discarded. The acid layer was made basic (pH~11) with 10% sodium hydroxide solution, saturated with salt and extracted with chloroform (3×100 mL). The aqueous layer was filtered and the filtrate was concentrated in vacuo. The residue was diluted with 40% aqueous isopropanol. The precipitate was faltered and dried to yield the title compound (0.2 g) as a colorless solid, m.p. 215°-217° C. [αD ]25 =-13.9° (c=0.42, DMF).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:20]([O-])=O)=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].CCO.[Cl-].[NH4+]>[Fe].O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c([N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c(N)s1
Temperature: 50 °C
Yield: 158.9 %

Procedure:
4-(3-Bromo-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (407 mg, 1.0 mmol, Example 20: step b) was dissolved into EtOH (6 mL). To this was added ammonium chloride (535 mg, 10 mmol) dissolved into water (3 mL). This mixture was heated to 50° C. with stirring and then iron (277 mg, 5 mmol) was added. The reaction was then heated to 80° C. with stirring for 12 hours. The reaction mixture was then filtered through Celite® and washed with 10% DCM/MeOH. Removal of the solvents in vacuo yielded the title compound (598 mg, quantitative yield) which was used without further purification. 1H-NMR (CDCl3): δ 8.05 (s, 1H), 7.84–7.86 (m, 1H), 7.70–7.75 (m, 1H), 7.56 (s, 1H), 7.40 (m, 1H), 6.02 (br s, 2H), 3.85 (s, 3H). ESI-MS (m/z): Calcd. for C12H10BrNO4S2: 375.9 (M+H); found: 376.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC.Cl[C:32]([O:34][CH3:35])=[O:33]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:35][O:34][C:32]([NH:1][CH2:2][CH2:3][O:4][CH:5]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH2:6][CH2:7][N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:33]
Reactant: CN(CCC(OCCN)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCOC(CCN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 36.4 %

Procedure:
To a 0° C. solution of tert-butyl 3-(2-aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (6 g, 4.11 mmol), Et3N (1.25 g, 12.3 mL), DMAP (0.25 g, 2.06 mmol) in dry CH2Cl2 (100 mL), methyl chloroformate (1.9 g, 20.6 mmol) in dry CH2Cl2 (30 mL) was added drop wise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. The reaction was quenched with water. The aqueous layer was extracted with CH2Cl2, the combined organic layers were washed with 10% citric acid and brine, then dried over Na2SO4, filtered and concentrated to the crude product. The crude product was purified by silica gel to afford tert-butyl 3-(2-(methoxycarbonyl)aminoethoxy)-3-(3-chlorophenyl)propyl(methyl)carbamate (600 mg, 40%). 1H NMR (CDCl3, 400 MHz) δ 1.49 (s, 9H), 1.83 (m, 2H), 2.80 (s, 3H), 3.31 (m, 7H), 3.65 (s, 3H), 4.13 (m, 1H), 7.26 (m, 4H).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>CN(C=O)C>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:25][C:26]#[N:27])[CH2:20][CH2:21][N:22]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:23][CH2:24]4)[CH:18]=3)[N:11]3[CH:28]=[CH:29][N:30]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCNCC4)c3)n2)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CCN(CC(F)(F)F)CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.7 %

Procedure:
2-(4-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidin-4-yl)acetonitrile hydrochloride (Example 28, Step A; 0.050 g, 0.11 mmol) was dissolved in DIEA (0.12 mL, 0.70 mmol) and DMF (0.2 mL) with sonication. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (0.025 g, 0.11 mmol) was added and the reaction was stirred at ambient temperature. After four hours the reaction was applied to a silica caplet and pumped to dryness. The caplet was applied to a silica column and eluted with 0.5-2% MeOH/DCM. The purified product was isolated to provide 2-(4-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)acetonitrile (5.0 mg, 10% yield) as a solid. MS (apci) m/z=470.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[F:12][C:9]1[CH:10]=[N:11][C:2]([CH3:13])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)cnc1Cl
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(F)cnc1C
Temperature: 110 °C
Yield: 70 %

Procedure:
A mixture of methyl 2-chloro-5-fluoronicotinate (step 1, 1.5 g, 7.91 mmol), tetrakis(triphenylphoshine)palladium (914 mg, 0.79 mmol), methyboronic acid (521 mg, 8.70 mmol) and potassium carbonate (3.28 g, 23.7 mmol) in 1,4-dioxane (20 ml) was heated at 110° C. for 20 h under nitrogen atmosphere. The reaction mixture was filtered through a pad of celite (Celite™ (diatomaceous earth)) and the filtrate was concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20/1 to 4/1) to afford 936 mg (64%) of the title compound:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([C:22]#[N:23])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.CC(O)=[O:26].Cl>CO.C(O[Pd]OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]3[C:12](=[C:11]([C:22]([NH2:23])=[O:26])[CH:10]=2)[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]3=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)O
Reactant: COc1cccc(-c2ccc(Nc3cccnc3)c(C#N)c2)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: Cl
Solvent: CO
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cccnc4c3c2)c1
Temperature: 160 °C
Reaction time: 0.33 h

Procedure:
To a 5 mL microwave vial 3′-methoxy-4-(pyridine-3-ylamino)biphenyl-3-carbonitrile (100.0 mg, 0.33 mmol), diacetoxypalladium (149.0 mg, 0.66 mmol) and AcOH (2 mL) were added. The vessel was sealed, and the reaction stirred at 160° C. 1 h. The reaction mixture was filtered and purified by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=80:20 and ending with A:B=0:100 [A=10% MeOH, 90% water, 0.1% TFA; B=90% MeOH, 10% water, 0.1% TFA] over 20 min). The HPLC fractions that contained the product were applied onto a cartridge of PHENOMENEX® Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and the product was eluted with a 2N solution of ammonia in methanol. The solvents were removed and the product was converted to the HCl salt by adding a (1 eq) solution of 1N HCl in methanol. The solvents were removed to afford 12.00 mg of 8-(3-methoxyphenyl)-5H-pyrido[3,2-b]indole-6-carboxamide, carboxamide, HCl. MS (ESI) m/z 318.2 (M+H). 1H NMR (MeOD) d ppm 8.77-8.85 (3H, m), 8.62 (1H, d, J=1.83 Hz), 8.06 (1H, dd, J=8.24, 5.80 Hz), 7.48 (1H, t, J=7.93 Hz), 7.39-7.44 (2H, m), 7.04 (1H, dd, J=8.09, 1.68 Hz), 3.93 (3H, s).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:19])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12](=[O:18])[NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH3:4].[CH2:20]1[S:22][CH2:21]1>O1CCCC1>[CH2:1]([NH:5][C:6](=[O:19])[CH2:7][CH2:8][N:9]([CH2:10][CH2:11][C:12](=[O:18])[NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:20][CH2:21][SH:22])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)CCNCCC(=O)NCCCC
Reactant: C1CS1
Solvent: C1CCOC1
Product: CCCCNC(=O)CCN(CCS)CCC(=O)NCCCC

Procedure:
Dissolve N-butyl-3-(2-butylcarbamoyl-ethylamino)-propionamide (10 mmol) prepared in Scheme VI, step D in tetrahydrofuran (50 mL) and add dropwise ethylene sulfide (22 mmol). Heat the reaction to reflux for 4 hours. After cooling, concentrate the reaction under vacuum and purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide N-butyl-3-[(2-butylcarbamoyl-ethyl)-(2-mercapto-ethyl)amino]-propionamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][C@@H:8]([NH2:38])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[C:1]([O:5][C:6](=[O:39])[CH2:7][C@H:8]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:37])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])=[O:26])=[C:20]([O:35][CH3:36])[CH:19]=2)=[CH:13][CH:14]=1)[NH:38][S:48]([CH3:47])(=[O:50])=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(CC(=O)Nc2ccc([C@H](N)CC(=O)OC(C)(C)C)cc2)ccc1NC(=O)Nc1ccccc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(CC(=O)Nc2ccc([C@@H](CC(=O)OC(C)(C)C)NS(C)(=O)=O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of (R)-3-amino-3-(4-{3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetylamino}-phenyl)-propanoic acid tert-butyl ester [100 mg, Reference Example 7(a)], dichloromethane (10 ml) and triethylamine (38 mg) was stirred at ambient temperature and then treated with methanesulphonyl chloride (22 mg). After stirring for 1 hour, the reaction mixture was diluted with dichloromethane (20 ml) and then washed with hydrochloric acid (20 ml, 1M), then with saturated aqueous sodium bicarbonate solution (20 ml). The organic layer was dried over magnesium sulphate and then evaporated to give the title compound (55 mg) as a white solid.