Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28]N(C)C=O.[H-].[Na+].CI>O>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH3:28])[C:18](=[O:20])[S:19]/2)=[CH:12][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C1NC(=O)/C(=C/c2cn(-c3ccccc3)nc2OCc2ccccc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)S/C(=C\c2cn(-c3ccccc3)nc2OCc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-1,3-thiazolidine-2,4-dione (1.30 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.15 g) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, methyl iodide (0.58 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hrs. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to give (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-3-methyl-1,3-thiazolidine-2,4-dione as yellow crystals (1.30 g, yield 98%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 226-227° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1)#[N:2].[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].[Al](Br)(Br)Br>>[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]1[N:18]=[C:17]([C:16]([Cl:20])([Cl:19])[Cl:15])[N:18]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#Cc1ccc(SCCC(=O)O)cc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: Br[Al](Br)Br
Product: O=C(O)CCSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Temperature: 60 °C

Procedure:
The reaction mixture of 22 g of 3-(4-cyanophenyl thio)propionic acid, 150 g of trichloroacetonitrile, and 2 g of AlBr3 was heated to 60° C. in order to dissolve the initially undissolved starting materials, and was bubbled by dry HCl at room temperature.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH2:14][OH:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]1.C(N(CC)CC)C>ClCCl>[CH:1]1([N:6]2[CH2:12][CH:11]([CH2:13][CH2:14][OH:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(CCO)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(CCO)C(=O)N2C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 143.4 %

Procedure:
A mixture of 0.047 g (0.0001 mole) of (rac)-4-[9-cyclopentyl-7-(2-hydroxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-49a), 0.043 g (0.00011 mole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.027 g (0.000023 mole) of 4-amino-1-methylpiperidine, 0.05 mL of triethylamine and 2 mL of dichloromethane was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The residue purified by C18 reverse phase silica gel chromatography, eluting with an acetonitrile-water gradient (10:90-100:0) to give 0.0182 g of (rac)-4-[9-cyclopentyl-7-(2-hydroxy-ethyl)-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-49)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:28])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH3:29][C:10]1([CH3:30])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH:11]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([CH3:28])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:17]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N(C)C(=O)N(C)C)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 36 h
Yield: 26.2 %

Procedure:
A mixture of 3,3-dimethyl-2-[3-(trimethyl-ureido)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (409 mg, 1 mmol) in methanol (5 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (5 mL) was stirred at 60° C. for 36 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(trimethyl-ureido)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 26%) as a yellow solid: LC/MS m/e calcd for C22H27N3O3 (M+H)+: 382.48, observed: 382.1.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[C:4]([C:3]1[C:2]([O:20][C:17]2[CH:18]=[CH:19][C:11]([F:10])=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: O=C(O)c1cc(O)ccc1F
Reactant: N#Cc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Temperature: 95 °C

Procedure:
To 2-chloronicotinonitrile (900 mg, 6.50 mmol), 2-fluoro-5-hydroxybenzoic acid (1.0 g, 6.4 mmol) and cesium carbonate (4.2 g, 13 mmol) was added DMSO (7 mL). The mixture was heated to 95° C. for 18 hours in a sealed tube. The mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified with 6 N HCl (pH˜2) and then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to yield 5-(3-cyanopyridin-2-yloxy)-2-fluorobenzoic acid. MS m/z 257=[M+H]+. Calc'd for C13H7FN2O3: 258.21.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:39](OCC)=[O:40].C(N(C(C)C)CC)(C)C>CO>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([CH:39]=[O:40])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Reactant: CCOC=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(C=O)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Temperature: 48 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
To a solution of 0.15 g (0.28 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) in methanol (0.5 mL) was added ethyl formate (3 mL) followed by diisopropylethylamine (0.2 mL, 1.1 mmol). The reaction mixture was stirred at 48° C. for 18 h and concentrated. The residue was purified using silica chromatography, eluting with a gradient of 1-5% MeOH/CH2Cl2 to afford (3S,4R)-N-tert-butoxy-1-formyl -3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (0.092 g, 58%). MS: 569.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:17]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@H:13]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NS(=O)(=O)c3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using 4-fluorobenzenesulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 538.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][O:9]2)=[CH:4][C:3]=1[F:17].C([Li])CCC.[CH:23](N1CCCCC1)=[O:24].Cl>C1COCC1.CCCCCC.O>[F:17][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH:23]=[O:24])[O:9][CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6]2
Reactant: CCCCCC1COc2cc(Br)c(F)cc2C1
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCC1COc2cc(C=O)c(F)cc2C1
Reaction time: 1 h

Procedure:
15.5 g (51.5 mmol) of 7-bromo-6-fluoro-3-pentylchroman are dissolved in 85 ml of THF, and 35 ml (55.7 mmol) of a 15 percent solution of n-butyllithium in n-hexane are slowly added at −70° C. After 1 h, 6.3 ml (56.7 mmol) of N-formylpiperidine in 15 ml of THF are added dropwise, and the mixture is stirred for 1 h. The batch is subsequently allowed to thaw, added to water, acidified using dil. hydrochloric acid and extracted three times with MTB ether. The combined org. phases are washed with water and sat. sodium chloride soln. and dried over sodium sulfate, the solvent is removed in vacuo, and the residue is recrystallised from heptane at −25° C., giving 6-fluoro-3-pentylchroman-7-carbaldehyde as colourless crystals (Rf=0.4; 1-chlorobutane).
Reaction SMILES: [CH:1]1([N:4](CC)[CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=2[CH3:14])[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)[CH3:18].[CH2:29](N(CC)CC)[CH3:30]>[Cu]I.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>[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([C:13]#[C:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][NH:4][CH2:1][CH:3]=[C:2]3[CH2:30][CH2:29]3)=[C:7]([CH3:14])[CH:8]=2)=[CH:23][CH:22]=1)[CH3:18]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(CN(CC)C2CC2)c(C)c1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCOC(=O)c1ccc(C#Cc2ccc(CNCC=C3CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; cyclopropyl-ethyl-(4-ethynyl-2-methyl-benzyl)-amine (Intermediate 161, 190.0 mg, 0.89 mmol) and ethyl-4-iodo benzoate (Reagent A, 245.0 mg, 0.89 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (56.0 mg, 0.30 mmol) and sparged with argon for 15 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (208 mg, 0.30 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (3-5% EtOAc-hexanes) afforded the title compound.
Reaction SMILES: Cl.[C:2]1([C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:14][CH:15]=2)=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][N:33]([CH2:35][C@H:36]3[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]3)[CH:34]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:8]([C:10]1[CH:15]=[N:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:23]3[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[N:32][N:33]([CH2:35][C@H:36]5[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]5)[CH:34]=4)[N:24]=3)[CH2:18][CH2:17]2)=[N:12][CH:11]=1)(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Reactant: O=C(c1ccccc1)c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C(=O)c6ccccc6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a mixture of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone HCl salt (141.6 mg, 0.38 mmol) and (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (150 mg, 0.38 mmol) in dioxane (10 mL) was added diisopropylethylamine (1 mL), and the reaction was stirred at room temperature overnight. LCMS showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give (S)-tert-butyl 2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (230 mg, 95%) as a yellowish solid. (MS (ES+) C31H37N11O4 requires: 627, found: 573 [M-56+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C@H:12]([NH:23]C(OCC2C=CC=CC=2)=O)[C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[N:8][CH:9]=1)([O-])=O.C.[H][H]>CO.O.[Pd]>[NH2:23][C@@H:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][N:8]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(N[C@@H](CCc1ccc([N+](=O)[O-])cn1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1ccc(CC[C@H](N)C(=O)O)nc1
Yield: 91.3 %

Procedure:
A mixture of 5.16 g (11.5 mmol) of phenylmethyl (S)-5-nitro-α-[[(phenylmethoxy)carbonyl]amino]-2-pyridinebutanoate, 2 g of active charcoal and 0.77 g of active palladium-on-charcoal in 100 ml of methanol and 100 ml of water is stirred for 4 days at 50 psi of hydrogen at room temperature. The reaction medium is filtered through a cake of Celite and the cake is rinsed with 3×50 ml of boiling water. The aqueous phases are combined and concentrated under reduced pressure. 2.05 g of (S)-α,5-diamino-2-pyridinebutanoic acid are thus obtained in the form of a white solid.
Reaction SMILES: Cl.Cl.Cl.C1(NC(C2C3C=C(C4C([Cl:25])=CN=C(NCCCN5CCN(C)CC5)N=4)SC=3C=CC=2)=O)CC1.[CH:37]1([NH:40][C:41]([C:43]2[C:51]3[CH:50]=[C:49]([C:52]4[C:57]([Br:58])=[CH:56][N:55]=[C:54]([Cl:59])[N:53]=4)[S:48][C:47]=3[CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:39][CH2:38]1.[CH3:60][C:61]1([CH3:72])[CH2:66][CH:65]([CH2:67][CH2:68][NH2:69])[CH2:64][C:63]([CH3:71])([CH3:70])[NH:62]1>>[ClH:25].[ClH:59].[CH:37]1([NH:40][C:41]([C:43]2[C:51]3[CH:50]=[C:49]([C:52]4[C:57]([Br:58])=[CH:56][N:55]=[C:54]([NH:69][CH2:68][CH2:67][CH:65]5[CH2:66][C:61]([CH3:72])([CH3:60])[NH:62][C:63]([CH3:71])([CH3:70])[CH2:64]5)[N:53]=4)[S:48][C:47]=3[CH:46]=[CH:45][CH:44]=2)=[O:42])[CH2:39][CH2:38]1
Reactant: CC1(C)CC(CCN)CC(C)(C)N1
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Agent: Cl
Product: CC1(C)CC(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC(C)(C)N1

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-(2,2,6,6-tetramethyl-piperidin-4-yl)-ethylamine and isolated as a yellow solid. ES+(m/z) 556 (79Br) and 558 (81Br) [M(free base)+H].
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH3:8][O:9][CH2:10][CH2:11][C:12]1[N:13]([CH2:33][CH2:34][CH3:35])[C:14]2[C:23]3[CH:22]=[CH:21][C:20]([O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:19][C:18]=3[N:17]=[C:16]([NH2:31])[C:15]=2[N:32]=1.O>C(Cl)(Cl)Cl.C(O)C>[NH2:31][C:16]1[C:15]2[N:32]=[C:12]([CH2:11][CH2:10][O:9][CH3:8])[N:13]([CH2:33][CH2:34][CH3:35])[C:14]=2[C:23]2[CH:22]=[CH:21][C:20]([O:24][CH:25]3[CH2:26][CH2:27][N:28]([C:6]([NH2:5])=[O:7])[CH2:29][CH2:30]3)=[CH:19][C:18]=2[N:17]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(N)=O)CC4)ccc3c21
Reaction time: 0.67 h

Procedure:
Trimethylsilylisocyanate (0.225 mL, 1.67 mmol) was added dropwise to a slurry of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (prepared as described in Part A of Example 388, 0.640 g, 1.67 mmol) in chloroform (16 mL) at 0° C. The reaction mixture was stirred for 40 minutes and water (10 mL) was added. The reaction mixture was stirred vigorously for 2 hours, diluted with 200 mL ethanol, and then concentrated under reduced pressure to approximately 100 mL. Another 100 mL ethanol was added and the solution was evaporated to afford a white solid that was recrystallized from ethanol to provide 0.625 g of 4-{[4-amino-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxamide as granular off-white crystals, mp 207-208.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH3:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.CN1CCOCC1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:28]([Cl:36])[CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH3:17])(=[O:33])=[O:34])=[C:28]([Cl:36])[CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)aniline (D4) (1.20 g, 5.09 mmol) in dichloromethane (35 ml) was treated with morpholinomethyl-polystyrene HL resin (2.43 g, 4.2 mmol/g loading, 10.21 mmol) and then the 4-bromo-2-chlorobenzenesulfonyl chloride (2.96 g, 10.21 mmol). The resulting solution was stirred at room temperature overnight. The resin and was filtered, washed with methanol, and the solvent evaporated in vacuo. The residue was then passed through an SCX column eluting first with methanol followed by 2M ammonia in methanol. The basic fractions were collectedand solvent evaporated in vacuo to afford a crude product which was purified further by chromatography using a Flashmaster using an elution gradient of 0 to 5% methanol in dichloromethane. The relevant fractions were collected, combined and the solvent evaporated in vacuo to afford the title compound (E104). MS (ES+) m/e 488/490/492 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C(CC)C.[CH3:41][S:42][C:43]1[N:48]=[C:47]([CH:49]=[O:50])[CH:46]=[CH:45][N:44]=1>C(OC)(C)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([CH:49]([C:47]2[CH:46]=[CH:45][N:44]=[C:43]([S:42][CH3:41])[N:48]=2)[OH:50])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1nccc(C=O)n1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Agent: [Li]C(C)CC
Solvent: COC(C)(C)C
Product: CSc1nccc(C(O)c2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(N3C[C@@H](C)O[C@H](C)C3)c(F)c2F)n1
Reaction time: 0.33 h
Yield: 34.5 %

Procedure:
Starting materials: (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 43, 7.36 g, 14.84 mmol) in t-BuOMe (20 mL) was added s-BuLi (12.45 mL, 16.19 mmol) at −75° C. under nitrogen atmosphere. After stirring for 20 minutes at this temperature, it was then transferred via cannula to a solution of 2-(methylthio)pyrimidine-4-carbaldehyde (2.08 g, 13.49 mmol) in t-BuOMe (20 mL) (precooled down to −70° C.), the mixture was then stirred for 0.5 hour at −70° C., quenched with saturated aqueouse ammonium chloride solution and extracted with ethylacetate, dried and concentrated, purified by flash column chromatography on silica gel with Hex/EtOAc to give the desired product (3.024 g).
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.C([Sn]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(CCCC)CCCC)CCC>CN(C=O)C.CCOCC>[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=Cc1cc(-c2cccs2)ccc1O
Temperature: 80 °C
Yield: 65.5 %

Procedure:
The synthesis of this compound is depicted schematically in FIG. 13. To a mixture of 5-bromosalicylaldehyde (2.847 g, 14.16 mmol) and Cl2Pd(PPh3)2 (0.497 g, 0.708 mmol, 0.05 equiv) was added tributylstannyl thiophene (6.75 mL, 21.24 mmol, 1.5 equiv) in 25 mL of DMF. The reaction mixture was heated at 80° C. 16 h, over which time the reaction color changed from light yellow to dark red. The reaction was cooled, diluted with Et2O and washed with dilute NH4Cl (4×150 mL). The organic layer was collected and filtered through a short silica pad to yield a yellow filtrate. The solvent was removed under reduced pressure to afford a gummy yellow solid, which was transferred to a frit and washed with hexanes. The yellow solid was dried in vacuo to afford 1.895 g (9.28 mmol, 66%) of a yellow powder (mp 102-103° C.). 1H NMR (CDCl3) δ11.01 (s, 1H), 9.96 (s, 1H), 7.80-7.76 (m, 2H), 7.29-7.24 (m, 2H), 7.11-7.07 (dd, 1H), 7.05-7.02 (dd, 1H). 13C NMR (CDCl3) δ196.5, 161.1, 142.7, 134.7, 130.8, 128.3, 127.1, 124.8, 123.0, 120.8, 118.4. MS m/z (204 (M+). HRMS (FAB) found m/z 205.0324 (M+H+); calcd for C11H9O2S m/z 205.0323 (M+H+).
Reaction SMILES: NCCN[C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[NH2:22][C@@H:23]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][OH:25]>>[OH:25][CH2:24][C@@H:23]([NH:22][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6])[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using (2S)-2-amino-4-methylpentan-1-ol instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 359 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, br. s.) 10.23 (1H, s) 8.00 (1H, d, J=5.37 Hz) 7.78 (1H, d, J=5.37 Hz) 7.62 (1H, d, J=8.59 Hz) 7.45 (1H, d, J=5.37 Hz) 7.30 (1H, dd, J=3.12, 1.85 Hz) 6.75 (1H, d, J=5.47 Hz) 6.42 (1H, d, J=2.73 Hz) 4.68 (1H, t, J=5.66 Hz) 4.05 (1H, td, J=9.42, 4.39 Hz) 3.36-3.47 (1H, m) 1.46-1.63 (1H, m, J=13.76, 6.82, 6.82, 6.65, 6.65 Hz) 1.23-1.45 (2H, m, J=13.36, 9.07, 9.07, 8.92, 4.59 Hz) 0.83 (6H, dd, J=6.54, 4.30 Hz)