Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH2:34])[CH3:31])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH:34][C:18]1[N:17]=[C:16]([C:13]2[S:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[CH:14]=2)[C:21]([Cl:22])=[CH:20][N:19]=1)[CH3:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1)C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 74.3 %

Procedure:
A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (406 mg, 1.12 mmol), (2-aminoethyl)-methylcarbamic acid tert-butyl ester (486 mg, 2.79 mmol) and diisopropylethylamine (432 mg, 3.34 mmol) in 1,4-dioxane (4 mL) is heated at 95° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with EtOAc in dichloromethane 0-35%, to give {2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-methylcarbamic acid tert-butyl ester as a foam (418 mg, 75% yield). The intermediate is then subjected to deprotection by dissolving this material (415 mg, 0.827 mmol) in MeOH (12 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (352 mg, 90% yield). ES+(m/z) 402 (35Cl) and 404 (37Cl) [M(free base)+H].
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8](/[CH:11]=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:19]([Mg]Cl)[CH3:20]>C1COCC1>[O:1]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:19][CH3:20])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: CC[Mg]Cl
Reactant: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Solvent: C1CCOC1
Product: CCC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-N-(1,4-dioxaspiro[4.5]decan-8-ylmethylene)-2-methylpropane-2-sulfinamide (as prepared in of Example 11 Step A, 3.66 g, 13.4 mmol) in dry THF (100 mL) was placed under an argon atmosphere and treated with ethylmagnesium chloride dropwise. After stirring at ambient temperature for 2 hours, the reaction mixture was cooled to −10° C. and cautiously quenched by the addition of saturated ammonium chloride solution. After dilution with water and ether extraction, the organic layer was concentrated in vacuo. Purification of the residue by flash chrom (silica gel, ethyl acetate) afforded the titled compound as a solid. 1H NMR (CHLOROFORM-d) δ: 3.80-4.00 (m, 4H), 2.85-3.15 (series of m, 2H), 1.71 (series of m, 11H), 1.20-1.25 (s, 9H), 0.97 (t, J=7.5 Hz, 3H)
Reaction SMILES: [CH:1]1([NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[CH:1]1([N:4]([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@H]1CC[C@H](NC2CC2)CC1
Reactant: COc1ccc(C(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(OC)cc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate (0.150 g, 0.710 mmol) in CH2Cl2 (2.5 mL) were added diisopropylethylamine (0.173 ml, 0.994 mmol), 4-methoxybenzoic acid (0.130 g, 0.852 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.470 g, 1.85 mmol) sequentially. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (50 mL), and then washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 18%-25% EtOAc-hexane. The desired amide product was obtained as a colorless oil (0.174 g). MS: 346 (M+1), C20H27NO4.
Reaction SMILES: C([O:4][CH:5]([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)(=O)C.[OH-].[Na+]>>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([OH:4])[CH3:16])=[CH:8][CH:9]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)Cc1ccc(C(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1ccc(CC(C)O)cc1
Yield: 104.4 %

Procedure:
2-Acetoxy-1-(4-acetylphenyl) propane (4.5 g) was heated for 2 hours in refluxing 2 N sodium hydroxide solution. The mixture was allowed to cool and the product was extracted into ether. Evaporation of the dried (MgSO4) extracts gave an oil (3.8 g).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[O:16])=[CH:13][C:12]([C:27]([F:30])([F:29])[F:28])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[O:16])=[CH:13][C:12]([C:27]([F:30])([F:28])[F:29])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)(=[O:1])[CH3:3]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C(C)O)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a stirred solution of 153 (650 mg, 1.550 mmol) in DCM (7.75 ml) under N2 was added Dess-Martin periodinane (0.50 ml, 1.627 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was taken to dryness and the residue was purified by chromatography (Biotage 15 to 65% EtOAc in hexane) to afford 154 (565 mg, 1.35 mmol, 88%). LRMS (ESI): (calc.) 417.1 (found) 440.2 (MNa)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]#[C:6][C:7](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:8]([F:11])(F)F)[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]2[C:8]([F:11])=[C:7]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:6]=[C:5]([CH:4]([O:3][CH2:1][CH3:2])[O:21][CH2:22][CH3:23])[N:30]=2)=[CH:27][CH:26]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(C#CC(=Nc1ccc(OC)cc1)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Temperature: 80 °C

Procedure:
In a typical reaction, N-(5,5-diethoxy-1,1,1-trifluoro-pent-3-yn-2-ylidene)-4-methoxyaniline is mixed with about a 2.5 to 3 fold excess of p-chlorobenzylamine and about a 2.5 to 3 fold excess of cesium carbonate in anhydrous tetrahydrofuran. The mixture is heated at about 80° C. until the reaction is complete. After cooling, an extraction solvent like a halogenated hydrocarbon is added to the mixture along with water. The organic layer is recovered, washed with brine and dried. The solvent is evaporated to provide crude 2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxyphenyl)pyridin-4-amine.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[C:25]2[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=2)[N:19]([CH3:27])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([NH2:16])=[N:18][N:19]2[CH3:27])=[CH:24][CH:23]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cn1nc(N)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3ccc4c(N)nn(C)c4c3)c2cc1OC
Temperature: 25 °C

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.60 g, 11.7 mmol), 3-amino-1-methyl-1H-indazol-6-ol (Step a, 2.72 g, 16.7 mmol) and cesium carbonate (Aldrich, 16.3 g, 50.1 mmol) in DMSO (16.7 mL, Aldrich) were stirred at 100° C. for 16 h. After cooling to RT, water was added. The aqueous layer was extracted with DCM. The organic phase was washed with water, dried with MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-100% of a 90:10:1 (CH2Cl2:MeOH:NH4OH) solution as the eluant afforded the title compound as a white solid. MS (ESI, pos. ion) m/z: 351.1 (M+1). Mass Calc'd for C19H18N4O3: 350.38.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[NH:21][CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([N:33]=[C:34]=[O:35])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]3[C:22](=[N:23][CH:24]=2)[N:21]([C:34]([NH:33][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:35])[CH2:20][CH2:19][CH2:18]3)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: c1ccc(COc2cncc(-c3cnc4c(c3)CCCN4)c2)cc1
Solvent: ClCCl
Product: O=C(NC(=O)N1CCCc2cc(-c3cncc(OCc4ccccc4)c3)cnc21)c1ccccc1
Yield: 78.5 %

Procedure:
To a solution of 6-(5-benzyloxy-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (530 mg, 1.7 mmol) in DCM (18 mL) is added benzoyl isocyanate (368 mg, 2.5 mmol). The resultant mixture is heated at reflux for 2 h. The solvent is removed under vacuum to obtain N-[6-(5-benzyloxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl]-benzamide (620 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:16]1=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:23])[C@@H:7]([N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]1=[O:22])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(N)c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.9 %

Procedure:
To a cooled (0° C.) solution of (S)-2-(3-amino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionic acid tert-butyl ester (2.6 g, 8.26 mmol) in dichloromethane (50 mL) was added triethylamine (918 mg, 9.09 mmol) and DMAP (20 mg) followed by dropwise addition of benzoyl chloride (1.27 g, 9.1 mmol). The reaction mixture was stirred at room temperature for 12 hours and then partitioned between EtOAc and sat. aqueous NH4Cl. The organic layer was washed with water (30 ml), brine (30 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (10-25% ethyl acetate/petrol ether) to afford the title compound as a colourless oil (2.07 g, 60%); 1H NMR (400 MHz, CDCl3) δ 1.48 (9H, s), 3.35 (1H, dd), 3.55 (1H, dd), 5.5 (1H, m), 6.26 (1H, t), 6.90 (1H, d), 7.15 (2H, m), 7.28 (3H, m), 7.52 (3H, m), 7.95 (2H, m), 8.52 (1H, d), 9.22 (1H, br s).
Reaction SMILES: [C:1]([O:15]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O.[NH:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20]>>[OH:20][CH2:19][CH2:18][N:17]([CH2:21][CH2:22][OH:23])[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([N:17]([CH2:21][CH2:22][OH:23])[CH2:18][CH2:19][OH:20])=[O:15]
Reactant: OCCNCCO
Reactant: COC(=O)CCCCCCCCC(=O)OC
Product: O=C(CCCCCCCCC(=O)N(CCO)CCO)N(CCO)CCO
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A mixture of 57.58 g (0.25 mol) dimethyl sebacate and 157.71 g (1.50 mol) of diethanolamine was heated in a 140° C. bath under nitrogen for 2.5 hrs while collecting the methanol condensate. The reaction mixture was subsequently heated in a 200° C. at reduced pressure (1.5 mm) to distill off excess diethanolamine. The highly viscous oily residue was dissolved in an equal volume of acetone and stirred overnight. The resulting crystalline solid was collected, washed with acetone, and dried. The yield of product was 35.0 g (9.3% of theory); mp=87-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH3:15])=[N:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>>[NH2:16][C:3]1[CH:4]=[C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH3:15])=[N:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1nnc(-c2ccc(Cl)c([N+](=O)[O-])c2)[nH]c1=O
Agent: Cl[Sn](Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc(Cl)c(N)c2)[nH]c1=O

Procedure:
This compound was obtained by reducing 3-(4-chloro-3-nitrophenyl)-6-methyl-4H-[1,2,4]triazin-5-one with tin chloride.
Reaction SMILES: C[C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[Br:9].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:17]12[CH2:22][CH:21]1[CH2:20][NH:19][CH2:18]2>CN(C=O)C>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:7][C:5]1[S:6][CH:2]=[C:3]([Br:9])[N:4]=1)[CH2:18]2
Reactant: Cc1sc(CBr)nc1Br
Reactant: C1NCC2CC12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1csc(CN2CC3CC3C2)n1
Yield: 78 %

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)thiazole (prepared according to the procedure reported in US 2010/298388, 0.60 g, 2.33 mmol) in DMF (5 ml) was added to a potassium carbonate (0.48 g, 3.50 mmol) and 3-azabicyclo[3.1.0]hexane hydrochloride (0.33 g, 2.80 mmol) at 0° C. under stirring. The reaction mixture was stirred at room temperature for 30 minutes. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (5 ml). The mixture was then extracted with ethyl acetate (2×25 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated from the dried organic layer under reduced pressure to obtain a crude product; the crud product was further purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.47 g, 78%). MS: m/z 261 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)=[O:7])([O-])=O.[H][H]>[C].[Pt].ClCCl>[NH2:1][C:4]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][N:10]=1)=[O:7]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)Nc2ccc(Cl)cn2)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: ClCCl
Product: COc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 28 °C
Reaction time: 16.5 h
Yield: 89.5 %

Procedure:
To a 780 L Hastelloy reactor, compound C (33 Kg, 1.0 eq), 5% platinum carbon (sulfided, 0.33 Kg, 0.010 parts) and dichloromethane (578 Kg, 17.5 parts) were charged. Agitation was started and reactor contents were adjusted to 22° C. (19 to 25° C.). The reactor was pressurized with ca. 30 psi hydrogen and the reaction mixture gently heated to 28° C. (25-31° C.). Hydrogenation of the reactor contents was performed under ca. 30 psi at 28° C. (25 to 31° C.; maximum 31° C.) until the reaction was complete by HPLC. After 16.5 hrs, the reaction was deemed complete after confirming the disappearance of starting material (0.472 A %). The contents of the reactor were circulated through a conditioned celite pad (0.2-0.5 Kg celite conditioned with 20-55 Kg dichloromethane) prepared in a 8″ sparkler filter to remove the platinum catalyst. The reactor and celite bed were rinsed forward with two portions of dichloromethane (83 Kg, 2.5 parts each). The filtrate was transferred to and concentrated in a 570 L GLMS reactor under a atmospheric pressure to ca. 132 L (4 parts volume). Ethanol (69 Kg, 2.1 parts) was charged and concentration continued under atmospheric pressure to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 39%. Ethanol (69 Kg, 2.1 parts) was charged again and concentration continued again to ca. 99 L (3 parts volume). In-process NMR indicated that the dichloromethane content was 5%. The reaction mixture was then adjusted to 3° C. (0 to 6° C.), agitated for ca. 1 hr, and the resulting slurry filtered onto a jacketed pressure nutsche fitted with F-19 filter cloth. The reactor, pump, and lines were rinsed forward with cold [3° C. (0-6° C.)] ethanol (26 Kg, 0.8 parts). The wet filter cake (36.6 Kg) was dried under vacuum at 40-50° C. with a maximum temperature of water bath (to heat reactor jacket) of 50° C. LOD analysis after 12.5 hrs indicated solvent content was at 0.1%. The dry product (D) was discharged (26.4 Kg) in 89.5% yield. HPLC showed 98.4 A % purity, with dechlorinated impurity at 0.083%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.ClC([C:13]([C:15]1[NH:16][C:17]([Br:21])=[C:18]([Br:20])[CH:19]=1)=[O:14])(Cl)Cl>C(#N)C>[Br:20][C:18]1[CH:19]=[C:15]([C:13]([NH:1][CH2:2][CH2:3][CH:4]2[O:8][CH2:7][CH2:6][O:5]2)=[O:14])[NH:16][C:17]=1[Br:21]
Reactant: NCCC1OCCO1
Reactant: O=C(c1cc(Br)c(Br)[nH]1)C(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(NCCC1OCCO1)c1cc(Br)c(Br)[nH]1

Procedure:
A solution of 2-(2-aminoethyl)-1,3-dioxolane (2.4 g, 20.6 mmol) and 4,5-dibromopyrrol-2-yl trichloromethyl ketone (7.6 g, 20.5 mmol) in 30 mL of acetonitrile was stirred at room temperature for 16 h. The reaction mixture was filtered and the precipitate 11 (6.8 g, 90%) was collected as a colorless solid: mp 155-157° C.; 1H NMR (CDCl3) d 1.99 (dt, 2H, J=6.0, 4.2), 3.61 (dt, 2H, J=6.0, 5.6), 3.92 (m, 2H), 4.05 (m, 2H), 5.00 (t, 1H, J=4.2), 6.51 (d, 1H, J=2.8), 6.66 (bs, 1H), 10.57 (bs, 1H); 13C NMR (CD3COCD3) d 34.3 (e), 35.5 (e), 65.4×2 (e), 99.4 (e), 103.4 (o), 105.4 (e), 113.0 (o), 129.1 (e), 160.0 (e); IR (nujol) 3358, 1646, 1569, 1412, 1372 cm−1; UV (CH3OH) lmax 275, 233, 214 (sh) nm; MS m/z (relative intensity) 371 (M++5, 50), 369 (M++3, 100), 367 (M++1, 50), 289 (13), 118 (25), 101 (50), 73 (30); Anal. Calcd for C8H10N2O2Br2: C, 32.63; H, 3.29; N, 7.61; Found: C, 32.77; H, 3.17; N, 7.51.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:11]3[C:10]3[C:5]2=[C:6]([OH:24])[CH:7]=[CH:8][CH:9]=3)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]#[N:34]>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([O:15][CH2:16][CH:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:11]3[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([O:24][CH2:32][C:33]#[N:34])[C:5]2=3)[CH:14]=1
Reactant: Cc1cc2c3c(c1)c1c(O)cccc1n3C(c1ccccc1)CO2
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c3c(c1)c1c(OCC#N)cccc1n3C(c1ccccc1)CO2
Temperature: 85 °C
Yield: 45.5 %

Procedure:
To a mixture of 5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (1.3 g, 4.12 mmol) in DMF (15 mL) is added potassium carbonate (2.8 g, 20.6 mmol) and bromoacetonitrile (1.4 mL, 20.6 mmol). The mixture is heated at 85° C. for 1.5 h. The mixture is cooled and partitioned between water and CH2Cl2. The organic layer is washed twice with water (200 mL), dried over magnesium sulfate and concentrated. Column chromatography (100 g silica gel) using ethyl acetate/hexanes (20/80) eluent gave 0.665 g (46%) of 2-[(5-methyl-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[C:7]([O:16][CH3:17])[C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[C:7]([O:16][CH3:17])[C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(-c2cccs2)cc(OC)c1C=O
Product: COc1cc(-c2cccs2)cc(OC)c1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 79 %

Procedure:
The title compound was prepared by condensing 2,6-dimethoxy-4-thiophen-2-yl-benzaldehyde (Ex-37A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, 79% yield, m.p. 256–258° C. 1H-NMR (300 MHz, d6-DMSO): 8.11 (d, 1H, J=15.9 Hz), 8.10 (m, 4H), 8.05 (d, 1H, J=15.9 Hz), 7.73 (d, 1H, J=3.6 Hz), 7.61 (d, 1H, J=5.3 Hz), 7.16 (dd, 1H, J=5.3 and 3.6 Hz), 6.95 (s, 2H), 3.98 (s, 6H). MS m/z=394 ([M]+, 100%). HRMS (EI) Calcd. for C22H18O5S: 394.0875. Found: 394.0877.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH2:33]>>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[N:15]([C:11]([C:9]4[CH:8]=[CH:7][N:6]=[C:5]([NH:33][CH2:32][C:28]5[S:27][CH:31]=[CH:30][CH:29]=5)[N:10]=4)=[CH:12][N:13]=3)[CH:16]=[CH:17][N:18]=2)[CH2:21][CH2:22]1
Reactant: NCc1cccs1
Reactant: CN1CCN(c2nccn3c(-c4ccnc(S(C)(=O)=O)n4)cnc23)CC1
Product: CN1CCN(c2nccn3c(-c4ccnc(NCc5cccs5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of 3-(2-methanesulfonyl-pyrimidin-4-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 46 supra) (150 mg, 0.402 mmol) and thiophen-2-ylmethanamine (182 mg, 1.608 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford the crude product (115 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford {4-[8-(4-methyl-piperazin-1-yl)-imidazo [1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-thiophen-2-ylmethyl-amine; hydrochloride. (Yield 34 mg, 21.2%). 1H NMR (300 MHz, CD3OD): δ 9.02 (brs, 1H), 8.84 (s, 1H), 8.39 (d, 1H, J=6.3 Hz), 7.69-7.63 (m, 2H), 7.40 (brs, 1H), 7.23 (s, 1H), 7.06-7.03 (m, 1H), 5.62-5.51 (m, 2H), 5.06-4.99 (m, 2H), 3.88-3.75 (m, 4H), 3.48-3.37 (m, 2H), 3.00 (s, 3H). LC-MS: [M+H]+ 407.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Clc1ccccc1CBr
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccccc4Cl)CC3)cccc2n1
Yield: 63 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-Chlorobenzyl bromide (76 mg; 0.37 mmol) to obtain 46.6 mg. (63% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 10.1 (s, 1H), 9.0 (s, 1H), 7.72 (t, J=8.0 Hz, 2H), 7.52 (m, 1H), 7.45 (m, 1H), 7.34 (m, 3H), 7.22 (d, J=8.0 Hz, 1H), 3.68 (s, 2H), 3.03 (br d, J=10.8 Hz, 2H), 2.93 (m, 4H), 2.41 (m, 2H).