Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCOCC.[Cl-].[CH2:16]([N+:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[C:25]([CH2:31][CH3:32])[CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([CH2:29][CH3:30])=[C:25]([CH2:31][CH3:32])[CH:24]1[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCc1cc[n+](Cc2ccccc2)cc1CC
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC1=C(CC)C(Cc2ccccc2)N(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
The Grignard reagent prepared from magnesium (85.5 g.), benzyl chloride (407 g.) and ether (3020 ml.) was added to the slurry of 1-benzyl-3,4-diethylpyridinium chloride in benzene (2250 ml.). After refluxing the mixture was quenched in ice and ammonium chloride (453 g.). Ammonium hydroxide was added to the mixture. The ether layer was washed with water and concentrated. A solution of sodium borohydride (52 g.) in water (260 ml.) was added to a solution of the residue (712 g.) in ethanol (2 l.). The mixture was stirred, allowed to stand overnight and filtered. The filtrate was concentrated under vacuum. Water and ether were added to the residue. The ether layer was washed with water, dried and concentrated. The residue was distilled under vacuum. The main fractions darkened on exposure to air. Therefore, the sodium borohydride reduction was repeated excluding water. Sodium borohydride (42 g.) was added portionwise with stirring to a solution of the combined main fractions (517 g.) in ethanol (100%, 1 l.). The mixture was stirred for 6 hours, allowed to stand overnight and concentrated. Water and ether were added. The ether layer was washed with water, dried and concentrated. Since the reduction still appeared incomplete, it was repeated using dimethylformamide as the solvent. Sodium borohydride (40 g.) was added portionwise to a solution of the residue in dimethylformamide (1 l.). The mixture was stirred and allowed to stand overnight. Water was added and the mixture was extracted with ether. The ether extracts were washed with water, dried and concentrated. The residue was distilled under vacuum, affording 1,2-dibenzyl-3,4-diethyl-1,2,5,6-tetrahydropyridine (172 g., b.r. 154°-178° C./0.1 mm., mostly at 174° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH:44]12[NH:51][CH:48]([CH2:49][CH2:50]1)[CH2:47][O:46][CH2:45]2>>[O:21]1[CH2:20][CH2:19][CH:18]([O:17][C:13]2[C:12]3[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:51]5[CH:44]6[CH2:50][CH2:49][CH:48]5[CH2:47][O:46][CH2:45]6)[CH:7]=4)=[N:9][NH:10][C:11]=3[CH:16]=[CH:15][N:14]=2)[CH2:23][CH2:22]1
Reactant: C1CC2COCC1N2
Reactant: Clc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Agent: Cl
Product: c1cc(-c2n[nH]c3ccnc(OC4CCOCC4)c23)cc(N2C3CCC2COC3)n1
Yield: 24 %

Procedure:
Prepared according to the procedure described in Example 111, by reacting 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride for 100 minutes in Step 1 to give the title compound (14.2 mg, 24% over two steps). LC-MS (Method G): m/z=408.1 [M+H]+; 3.32 min. 1H-NMR (400 MHz, DMSO): δ 13.40 (s, 1H), 8.19 (d, J=4.3, 1H), 7.90 (d, J=5.7, 1H), 7.28 (s, 1H), 7.24-7.13 (m, 2H), 5.54-5.45 (m, 1H), 4.51 (s, 2H), 3.86-3.73 (m, 2H), 3.70 (d, J=10.6, 2H), 3.59-3.46 (m, 4H), 2.13-2.01 (m, 2H), 2.01-1.93 (m, J=6.9, 2H), 1.93-1.84 (m, 2H), 1.76-1.60 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:26])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8].[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][C:33]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:34])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:13]([C:15]([CH3:18])([CH3:16])[CH3:17])[N:14]=1)=[O:8]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CC(C)(C)C(=O)c1sc(NC(=O)c2cc(Cl)ccc2O)nc1C(C)(C)C
Product: CC(C)(C)C(=O)c1sc(NC(=O)c2cc(Cl)ccc2OC(=O)N2CCOCC2)nc1C(C)(C)C
Yield: 93.1 %

Procedure:
Using 5-chloro-N-{4-[(1,1-dimethyl)ethyl]-5-[(2,2-dimethyl)propionyl]-thiazol-2-yl}-2-hydroxybenzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:4]=[C:3]1[CH:21]=[O:22].[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[CH:4]=[C:3]1[CH:21]=[O:22]
Reactant: CCOC(=O)c1c(COc2cccc(C)c2)cc(C=O)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(OCc2cc(C=O)n(C)c2C(=O)O)c1

Procedure:
A sample of ethyl 1-methyl-2-formyl-4-(3-methylphenoxymethyl)pyrrole-5-carboxylate (3.24 g, 10 mmol) is dissolved in hot ethanol (50 ml) and 10% aqueous NaOH is added (10 ml). The resulting mixture is heated at reflux until all starting material has been consumed. The solution is cooled, diluted with water (140 ml) and acidified to pH 2 with 6 N HCl. The resulting two-phase mixture is extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers are then washed with saturated brine (50 ml), and dried over sodium sulfate. The solvent is removed to give a residue which crystallizes on standing. This material is sufficiently pure for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][CH:8]=[N:7][CH:6]=2.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[O:29]>O1CCCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:28]([NH:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])=[O:29]
Reactant: Nc1cnc2cnccc2c1-c1ccccc1Cl
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)cc1F)Nc1cnc2cnccc2c1-c1ccccc1Cl
Yield: 36.4 %

Procedure:
A solution of 3-amino-4-(2-chlorophenyl)-1,7-naphthyridine (169 mg, 0.66 mmol) and 2,4-difluorophenylisocyanate (102 mg, 0.66 mmol) in tetrahydrofuran (50 ml) was refluxed for 8 hours. The mixture was concentrated, and the residue was purified by column chromatography (silica gel; methanol:chloroform=1:9), and recrystallized from hexane to give the title compound (98 mg, 0.24 mmol) as colorless powder.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:20])[N:8]=2)[CH:6]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:25]4[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=4)[N:3]=[CH:4]3)[N:12]=2)=[CH:14][CH:15]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.12) (0.14 g, 0.4 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.088 g, 0.4 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.045 g, 31%). MS (ISP) 363.1 [(M+H)+]; mp 206-208° C.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13](=[O:27])[CH2:14][C@H:15]3[C@H:20]([O:21]C)[CH2:19][CH2:18][CH2:17][N:16]3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[N:5][C:4]=2[C:3]=1[Cl:28].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][C:13](=[O:27])[CH2:14][C@H:15]3[C@H:20]([OH:21])[CH2:19][CH2:18][CH2:17][N:16]3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[N:5][C:4]=2[C:3]=1[Cl:28]
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(Cl)c(Cl)sc2c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N1CCC[C@@H](O)[C@@H]1CC(=O)Cn1cnc2c(Cl)c(Cl)sc2c1=O
Reaction time: 0.17 h

Procedure:
A 35 ml single neck round bottom flask equipped with a magnetic stirring bar was flame dried and then stoppered with a serum cap. Through a syringe needle the flask was evacuated and filled with dry nitrogen four times. A solution of 0.270 g (0.0006 mole) of methyl trans-2-[3-(6,7-dichloro-3,4-dihydro-4-oxothieno[3,2-d]pyrimidin-3-yl)-2-oxopropyl]-3-methoxy-1-piperidinecarboxylate and 10 ml of dichloromethane was injected into the reaction flask, and with stirring the temperature was lowered to -70° C. Again with a syringe 3.0 ml of 1.0M boron tribromide in dichloromethane (Aldrich Chemical Co.) was introduced into the reaction vessel. After 10 minutes the reaction temperature was allowed to rise to -10° C. and was held there for 150 minutes. There was then added 11 ml of saturated aqueous sodium bicarbonate to the reaction mixture. A small amount of solid matter was filtered, and the layers of the filtrate were separated. The aqueous phase was extracted three times with 5 ml portions of dichloromethane. The extracts were combined with the organic layer, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to furnish the title compound as an off white solid: yield 0.190 g (73%); mass spectrum peaks 434 (molecular ion), 415 (--1, --18, --H, --H2O), 195, 126 (parent) among others; 1H-nmr (CDCl3) delta 1.2-2.0 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.85 (doublet, 2H, COCH2CH), 3.0 (broad triplet, 2H, NCH2), 3.7 (singlet 3H, CO2CH3), 3.9-4.0 (multiplet, 2H, CH2CHNCO and OH), 4.7 (triplet with fine splitting, 1H, CHOCH3), 4.9-5.2 (multiplet, 2H, NCH2CO), 8.1 (singlet, 1H, N=CH--N).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C@H:12]([NH:14][S@@](C(C)(C)C)=O)[CH3:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[ClH:21].CO>>[ClH:21].[ClH:21].[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C@H:12]([NH2:14])[CH3:13])=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(OCC2CC2)cn1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
(R)-N-((R)-1-(5-(cyclopropylmethoxy)pyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (3.2 g, 10.9 mmol) was dissolved in 10N HCl/MeOH (50 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated by N2-flow to give the white precipitate. The solid was collected by filtration and washed with diisopropyl ether to give 3.2 g (49% yield) of the title compound as a white solid:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1C=O.Br[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].C1OCCOCCOCCOCCOCC[O:18][CH2:17]1>O1CCCC1>[CH2:11]([N:5]1[CH:6]=[C:7]([CH:17]=[O:18])[N:3]=[CH:4]1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: O=Cc1ncc[nH]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCn1cnc(C=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium hydride (20 g, 60% dispersion in mineral oil, 0.5 mol) in tetrahydrofuran (300 ml) was cooled to 0° C., and 2-imidazolecarboxaldehyde (45 g, 0.47 mol) was added portionwise over 30 minutes. Once addition was complete, the reaction was stirred at 0° C. for 30 minutes, then allowed to warm to room temperature. 1-Bromo-3-methylbutane (60.8 ml, 0.5 mol) and 18-crown-6 (140 mg) were added, and the reaction was heated at reflux for 18 hours. The cooled reaction was quenched by the addition of water (400 ml), and the resulting mixture extracted with dichloromethane (800 ml in total). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane:methanol (40:60:0 to 100:0:0 to 98:0:2) to afford the title compound, 19.6 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]#N)=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[OH-:25].[Na+].[OH2:27].Cl>C(O)C>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:27])=[O:25])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C#N)cc3)ccc21
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C(=O)O)cc3)ccc21

Procedure:
20 g (0.063 mol) of 4-cyanobenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether were refluxed with 163 ml of 10N sodium hydroxide solution in 245 ml of ethanol for 2 h. The mixture was cooled and then poured into water, which was then acidified with hydrochloric acid, and the precipitate was filtered off with suction and washed with water and methanol. Drying resulted in 19.7 g of the title compound of melting point >330° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:15]([CH:16]=C)[CH2:14][O:13][C:5]2=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.I([O-])(=O)(=O)=[O:19].[Na+]>C(O)CCC.CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH:16]([CH:15]1[C:4]2[C:5](=[C:6]3[C:11](=[C:2]([CH3:1])[CH:3]=2)[NH:10][C:9](=[O:12])[CH:8]=[CH:7]3)[O:13][CH2:14]1)=[O:19]
Reactant: C=CC1COc2c1cc(C)c1[nH]c(=O)ccc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OCC2C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
5-Methyl-2,3,6,7-tetrahydro-3-vinylfuro[2,3-f]quinoline-7-one (1.75 g) was dissolved in a mixture of butanol-acetone-water (3:3:1, 350 ml), to which sodium periodate (11.5 g) and osmium tetraoxide (350 mg) were added, followed by stirring at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was subjected to distillation to remove the solvent. The residue was recrystallized from a solvent mixture of chloroform-ether to obtain 1.05 g of 3-formyl-5-methyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as pale yellow needles (59.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([O:18]C)=[O:17])=[C:9]2[CH3:20])=[CH:4][CH:3]=1>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[C:9]2[CH3:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C)n(-c2ccc(Cl)cc2)c(C)cc1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(C(=O)O)c(C)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
16 g of N-(4-chlorophenyl)-3-carbomethoxy-2,6-dimethylpyrid-4-one is suspended in 450 g of 5% aqueous sodium hydroxide and stirred at room temperature for 24 hours. Acidification yields 14.2 g of N-(4-chlorophenyl)-3-carboxy-2,6-dimethylpyrid-4-one (m.p. 260°-61.5° decomp.) which is converted to its sodium salt (m.p. >310°) by neutralization with sodium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[Cl:56]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][O:53][CH2:54][CH2:55]6)=[O:49])=[CH:44][C:43]=5[Cl:56])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=C(c1ccc(Br)c(Cl)c1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCOCC4)cc3Cl)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and (4-bromo-3-chloro-phenyl)-morpholin-4-yl-methanone (59 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-chloro-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-309) as a pale brown powder (42 mg, 62%).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5](C(F)(F)F)=[CH:4][CH:3]=1.FC1C2SC(I)=NC=2C=CC=1>>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Agent: Fc1cccc2nc(I)sc12
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cccc(F)c2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 7-fluoro-2-iodo-1,3-benzothiazole and conducting the Suzuki coupling at 50° C. for 1.5 h, the title compound was obtained as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=8.84 (d, J=2.0 Hz, 1H), 8.41 (m, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 8.04 (dd, J=0.8, 8.0 Hz, 1H), 7.66 (m, 1H), 7.38 (m, 1H), 4.66 (m, 1H), 3.62 (dt, J=3.2, 13.2, 2H), 3.24-3.28 (m, 2H), 2.36-2.40 (m, 4H). MS(ES+): m/z=395.12 [MH+]. HPLC: tR=1.62 min (polar—5 min, ZQ3).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:15]([C:25]([OH:27])=O)=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl-].[Li+].[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[O:36]=[S:33]1(=[O:37])[CH2:34][CH2:35][N:30]([C:25]([C:15]2[N:16]([CH2:20][C:21]([F:22])([F:24])[F:23])[C:17]3[C:13]([CH:14]=2)=[CH:12][C:11]([O:10][CH:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[CH:19][CH:18]=3)=[O:27])[CH2:31][CH2:32]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)O)n3CC(F)(F)F)CC1
Reactant: O=S1(=O)CCNCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A mixture of 5-(1-isopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid, hydrochloric salt with one equivalent of lithium chloride (650 mg, 1.0 eq.), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurunium tetrafluoroborate (563 mg, 1.2 eq.), thiomorpholine-1,1-dioxide (purchased at Syntec, ref. M1201) and diisopropylethylamine (1.22 mL, 5 eq.) in dimethylformamide was stirred at room temperature for 24 h and then partitioned between an aqueous solution of sodium hydrogenocarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, evaporated in vacuo and purified on silica eluting with dichloromethane/methanol/ammoniac. One fraction was isolated and dried in vacuo, to yield 468 mg (66%) of the desired product as off-white solid. MS (m/e): 502.5 (MH+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.CO>[Fe].O>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(Sc2nc[nH]n2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: Nc1ccc(Sc2nc[nH]n2)cc1N

Procedure:
A mixture of 3.2 g. 2-amino-1-nitro-4-(1,2,4-triazol-3-ylthio)benzene, 3.2 g. of iron powder, 1.6 g. ferrous sulfate in 240 ml. methanol and 60 ml. water is refluxed for 6 hours (with one additional portion of iron being added after 3 hours. The mixture is cooled, filtered and the filtrate stripped under vacuum to yield 1,2-diamino-4-(1,2,4-triazol-3-ylthio)benzene.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24].CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: COCC(=O)Cl
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: COCC(=O)N(C)Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 52 %

Procedure:
1-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 55 from Example 11a (0.22 g) was reacted with methoxyacetyl chloride (1.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 52.7 mg of 403 after RP-HPLC purification (52% yield). MS (Q1) 453.2 (M)+
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])([CH3:5])[C:3]#[N:4].B>C1COCC1>[CH3:5][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])([CH3:1])[CH2:3][NH2:4]
Reactant: CC(C)(C#N)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the solid 2-methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propionitrile (1.0 g, 3.9 mmol) in a 250 mL round-bottom flask at 0 degrees C. was added a solution of borane in THF (47 mL of a 1 M solution in THF, 47 mmol). The orange-yellow solution was allowed to warm to room temperature and stir for 6 h. The solution was then cooled to 0 degrees C., and was quenched by the careful dropwise addition of 6 N HCl. After gas evolution ceased, a total of 47 mL 6N HCl was added, resulting in a white precipitate. The mixture was concentrated in vacuo to ½ the original volume, and was basified at 0 degrees C. with 6N NaOH. The mixture was extracted with a 100 mL portion of ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil. Purification by flash chromatography provided the desired product which contained minor impurities by NMR. MS m/z 263=[M+H]+. Calc'd for C11H13F3N2O2: 262.23.