Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCCC1.CO.O.[OH-].[Li+]>O>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(CN2CCCCC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN2CCCCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.1 %

Procedure:
To a solution of methyl 2-methyl-4-(piperidin-1-ylmethyl)benzoate (1.8 g, 7.3 mmol) in the mixture solution of tetrahydrofuran:methanol:water=3:1:1 (20 mL) was added lithium hydroxide monohydrate (1 g, 42 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and quenched with hydrochloride acid aqueous (1N, 5 mL). To the residue, water (50 mL) was added. The mixture was extracted with dichloromethane (50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, methanol/dichloromethane=1:15) to give the product 2-methyl-4-(piperidin-1-ylmethyl)benzoic acid (360 mg, 21%) as pale solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)=[N:8][C:9](=O)[C:5]=2[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)=[N:3]1.[C:25](=[O:28])([O-])[O-].[K+].[K+].[C:31]1(C)C=CC(S(OC)(=O)=O)=CC=1.[N+](C1C=CC=CC=1)([O-])=O>>[O:1]=[C:2]1[C:6]2=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH3:9])[C:25](=[O:28])[C:5]2=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[N:3]1[CH3:31]
Reactant: O=C([O-])[O-]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: Cc1cccc(-c2nc(=O)c3c(-c4cccc(C)c4)nc(=O)c2=3)c1
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cccc(C2=C3C(=O)N(C)C(c4cccc(C)c4)=C3C(=O)N2C)c1

Procedure:
9.5 Parts of 1,4-diketo-3,6-di-(3'-methylphenyl)pyrrolo-[3,4-c]pyrrole, 9 parts of anhydrous potassium carbonate and 24 parts of methyl p-toluenesulfonate are heated at 190° C. with 85 parts of nitrobenzene for 1 hour, with stirring. The cooled reaction mixture is filtered. The dye formed remains dissolved in the solvent. The nitrobenzene is removed by means of steam distillation and the crude dye is purified by crystallisation from 45 parts of toluene. 3.8 parts of 1,4-diketo-2,5-dimethyl-3,6-di-(3'-methylphenyl)pyrrolo-[3,4-c]-pyrrole are obtained in the form of orange crystals of melting point 195°-197° C. (formula XIII). The dye gives a pure yellow shade of good fastness properties on PES by the method described in Example 1b. ##STR17##
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19]([O:21]C)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al](CC)(CC)[CH2:24][CH3:25].CNCCNC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([C:19](=[O:21])[CH2:24][CH3:25])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC[Al](CC)CC
Agent: CNCCNC
Solvent: Cc1ccccc1
Product: CCC(=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure O, methyl 5,6-diphenyl-pyrazine-2-carboxylate (Compound 93) (92 mg, 0.32 mmol), Et3Al (0.9 ml, 1M in hexane), DMEDA (38 mg, 0.35 mmol) in toluene was reacted to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([OH:6])=O.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH3:35][C@@H:36]1[CH2:41][CH2:40][CH2:39][NH:38][C@@H:37]1[CH2:42][N:43]1[C:51](=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]1=[O:53]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[C:3]=1[C:4]([N:38]1[CH2:39][CH2:40][CH2:41][C@@H:36]([CH3:35])[C@H:37]1[CH2:42][N:43]1[C:51](=[O:52])[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:44]1=[O:53])=[O:6]
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: O=C(O)c1c(F)cccc1-c1ncccn1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 15.5 %

Procedure:
A solution of 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (366 mg, 1.67 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (292 mg, 1.67 mmol), and N-methylmorpholine (421 mg, 4.18 mmol) in anhydrous 1,4-dioxane (10 mL) was stirred at rt under nitrogen for 1.5 h. A solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (359 mg, 1.39 mmol) in anhydrous 1,4-dioxane (3 mL) was added at rt. After the addition was completed, the reaction was heated to 80° C. under nitrogen for 5 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), subsequently washed with 0.1 N HCl (100 mL), 0.1 N NaOH (100 mL), and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) to afford the title compound as a white foam (99 mg, 15%). ESI MS (M+H) 459.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[C:23]([CH3:24])=[CH:22][CH:21]=[C:20]4[C:15]=3[CH:16]=[CH:17][N:18]=[C:19]4[NH:25][C:26]3[CH:34]=[C:33]4[C:29]([CH:30]=[N:31][N:32]4C(OC(C)(C)C)=O)=[CH:28][CH:27]=3)=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[ClH:42]>C(OCC)(=O)C>[ClH:42].[NH:32]1[C:33]2[C:29](=[CH:28][CH:27]=[C:26]([NH:25][C:19]3[C:20]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[C:4]6[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=6[S:10][CH:9]=5)=[O:12])[C:23]([CH3:24])=[CH:22][CH:21]=4)[CH:16]=[CH:17][N:18]=3)[CH:34]=2)[CH:30]=[N:31]1
Reactant: Cc1ccc2c(Nc3ccc4cnn(C(=O)OC(C)(C)C)c4c3)nccc2c1NC(=O)c1csc2c(N)ncnc12
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2c(Nc3ccc4cn[nH]c4c3)nccc2c1NC(=O)c1csc2c(N)ncnc12
Reaction time: 5 h
Yield: 90 %

Procedure:
tert-butyl 6-((5-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-6-methylisoquinolin-1-yl)amino)-1H-indazol-1-carboxylate (50 mg, 0.088 mmol) obtained in Example 113 was dissolved in ethyl acetate (5 mL), and added with 4 M HCl (dioxane solution, 0.5 mL). The reaction solution was stirred for 5 hours, and then the filtrate was filtered to obtain the title compound (40 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SC)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH3:31][O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][CH:33]([O:32][CH3:31])[CH2:34][CH2:35]5)=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:28])([F:29])[F:30])[CH:3]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC1CCNCC1
Product: COC1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methoxy-piperidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 4-methoxy-piperidine following General Procedure B.
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[C:5]1[CH2:13][C:14]([O:16][CH3:17])=[O:15].[H-].[Na+]>CN(C)C=O>[CH:13]1([C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[C:5]12
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn2c1C(C(=O)OC)CC2
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of 1 g of methyl N-(2-iodoethyl)-3-carbomethoxypyrrole-2-acetate in 5 ml of dry dimethylformamide is stirred, under an atmosphere of argon, with 137 mg of 50% sodium hydride in mineral oil. The reaction mixture is maintained for 20 minutes at room temperature and then quenched with 100 ml of water. The product is extracted with ethyl acetate (3×50 ml), the combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue on 20 g of silica gel using hexane:ethyl acetate (4:1) as eluant, affords 500 mg (80%) of dimethyl 1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1,7-dicarboxylate (VII, R=H) m.p. 70°-71° C.
Reaction SMILES: [OH:1]O.[CH3:3][N:4]([CH3:20])[S:5]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)(=[O:7])=[O:6].[OH-].[Na+].[Cl-].[Na+]>C(O)C.O>[CH3:3][N:4]([CH3:20])[S:5]([C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:1])=[C:10]([C:16]([F:17])([F:19])[F:18])[CH:9]=1)(=[O:6])=[O:7]
Reactant: OO
Reactant: CN(C)S(=O)(=O)c1ccc(C#N)c(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1

Procedure:
Hydrogen peroxide (30%, 100 ml) was added to a stirred mixture of 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzonitrile (20.37 g) and sodium hydroxide (1.0 g) in ethanol under an inept atmosphere maintaining the temperature at 40°-45° C. The mixture was stirred and heated at that temperature for 3.5 hours. It was cooled, poured into water, sodium chloride was added and it was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was re-crystallized from a mixture of ethyl acetate and toluene to give 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzamide (16.44 g) as white crystals, m.p. 149°-156° C.
Reaction SMILES: [C:1]1([CH:7]([NH:10]C(=O)C(Cl)(Cl)Cl)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH:7]([NH2:10])[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(NC(=O)C(Cl)(Cl)Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CC(N)c1ccccc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
Amid 3 (13.9 g, 49.9 mmol), prepared as described in Example 2, was dissolved in 267 ml of distillated ethanol and 240 ml of 6 M aqueous solution of NaOH was added to the solution. The reaction mixture was stirred at 20° C. for 72 h, evaporated to aqueous remain which was acidified with 5 M HCl to pH=2. It was extracted twice with 100 ml dichloromethane. The aqueous layer was alkalified with sodium carbonate to pH=8 and extracted three times with 100 ml diethyl-ether. Organic layers were combined and dried over anhydrous sodium sulphate. By filtration and evaporation, the yield was 3.19 g (48%) of yellow oil; 1H NMR (CDCl3) δ: 1.69 (2H, bs, NH2), 4.52 (1H, d, J=5.8 Hz, CHNH2), 5.11 (1H, d, J=10.2 Hz, CHCH2), 5.24 (1H, d, J=17.2 Hz, CHCH2), 6.03 (1H, m, CHCH2), 7.33-7.35 (5H, m, ArH) ppm; 13C NMR (CDCl3) δ: 55.9 (CNH), 114.8 (CH2), 126.3 (CPh), 127.4 (2×CPh), 128.2 (2×CPh), 134.7 (CCH2) ppm.
Reaction SMILES: [CH3:1][C:2]([NH:13][CH2:14][C:15]1[C:20]([CH2:21][OH:22])=[C:19]([O:23]CC2C=CC=CC=2)[CH:18]=[CH:17][C:16]=1[CH2:31][OH:32])([CH3:12])[CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C.[Pd]>[CH3:12][C:2]([NH:13][CH2:14][C:15]1[C:20]([CH2:21][OH:22])=[C:19]([OH:23])[CH:18]=[CH:17][C:16]=1[CH2:31][OH:32])([CH3:1])[CH2:3][N:4]([CH3:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CN(CC(C)(C)NCc1c(CO)ccc(OCc2ccccc2)c1CO)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CN(CC(C)(C)NCc1c(CO)ccc(O)c1CO)c1ccccc1

Procedure:
α1 -[[[1,1-Dimethyl-2-(methylphenylamino)ethyl]amino]methyl]-4-phenylmethoxy-1,3-benzenedimethanol (1.3 g) in ethanol (60 ml) was hydrogenated over 10% palladium on charcoal (250 mg). The catalyst was filtered off and the filtrate was evaporated to an oil which foamed under high vacuum. The product crystallised as a white microcrystalline powder from dry ether (630 mg) m.p. 131°-133°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.Cl.Cl[CH2:16][CH2:17][N:18]([CH2:26][CH2:27]Cl)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:18]1[CH2:26][CH2:27][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=2)([C:10]#[N:11])[CH2:16][CH2:17]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1ccc(C(F)(F)F)cc1
Agent: Cl
Product: N#CC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1

Procedure:
Prepare by the method of example 76.1 using 4-trifluoromethylphenyl-acetonitrile (1.5 g, 8.1 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (1.9 g, 8.1 mmol) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[NH:14][C:13]3[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=3[N:11]=2)=[CH:4][CH:3]=1.C[O-].[Na+].[C:23](OC)(=[O:26])[C:24]#[CH:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[CH:25]=[CH:24][C:23](=[O:26])[N:14]3[C:13]4[CH2:15][CH2:16][CH2:17][CH2:18][C:12]=4[NH:11][C:10]=23)=[O:19])=[CH:4][CH:3]=1
Reactant: C#CC(=O)OC
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1ccc(F)cc1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 450 mg (1.74 mmol) of 1-(4-Fluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXXIV), 188.2 mg (3.84 mmol) of sodium methylate and 146.5 mg (1.74 mmol) methyl propiolate.
Reaction SMILES: S(Cl)(Cl)=O.C(N(C(C)C)C(C)C)C.[CH:14]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[CH3:27][CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1.[C:33]1(C)[CH:38]=CC=[CH:35][CH:34]=1>O>[CH:21]1([N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:30](=[O:29])/[CH:31]=[CH:32]/[C:28]2[CH:35]=[CH:34][CH:33]=[CH:38][CH:27]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: CC1CCCO1
Reactant: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: O=C(/C=C/c1ccccc1)N(c1ccccc1)C1CCCCC1
Temperature: 50 °C
Yield: 68 %

Procedure:
7.60 g (0.051 mol) of cinammic acid, 92 ml of toluene and 0.41 g (5.6 mmol) g of N,N-dimethylormamide are provided and mixed with 7.3 g (0.062 mol) of thionyl chloride. Stirring takes place for 1 hour followed by heating to 50° C. The toluene and excess thionyl chloride are drawn off under vacuum. Then 22 ml of toluene and 7.3 g (0.056 mol) of ethyldiisopropylamine are added at 60° C. A solution of 9.1 g (0.056 mol) of N-cyclohexylaniline in toluene is added and stirred for 1 hour at 60° C. Hydrolysis with water at 50° C. is performed and 2-methyltetrahydrofuran is added. The organic phase is separated and washed with water, 1N hydrochloric acid, 1N NaOH and again with water. The organic phase is rotated and the residue crystallised from n-heptane/MTBE. The crystallised solid is drawn off, washed with n-heptane and dried, wherein the desired compound is obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(OCC)(=O)C>CCCCCCC>[CH:1](=[N:9][C:10]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C#N)c(N)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccc(C#N)c(N=Cc2ccccc2)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
Benzaldehyde(8.9 g, 84 mmol) is added to a suspension of 2-amino-4-methylbenzonitrile (10.0 g, 76 mmol) in heptane (250 mL), and the mixture refluxed under nitrogen overnight. The hot solution is decanted into a pre-warmed flask to leave the insoluble brown oil material behind, and the solution cooled to room temperature after adding ethyl acetate (2 mL). The resulting solid is filtered off and washed with heptane:ethyl acetate=100:1 (2×25 mL), and dried under high vacuum to give a beige powder (12.54 g, 57 mmol).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH3:24])[CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidine (example E.51) (0.20 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a light brown solid (0.034 g, 17%). MS (ISP) 411.0 [(M+H)+]; mp 247.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][OH:7])[CH2:4][OH:5].[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[OH2:19]>N1C=CC=CC=1>[C:10]1([O:9][C:8]([O:5][CH2:4][CH:3]([CH2:6][O:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:19])[O:2][CH3:1])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC(CO)CO
Reactant: O
Agent: Cl
Solvent: c1ccncc1
Product: COC(COC(=O)Oc1ccccc1)COC(=O)Oc1ccccc1
Reaction time: 2 h

Procedure:
20 g of 2-methoxy-1,3-propanediol was dissolved in 200 ml of pyridine. 52.6 ml of phenyl chlorocarbonate was added dropwise to the solution under stirring and under cooling with ice. After two hours, the reaction solution was added to 1 l of 4N hydrochloric acid/water. After extraction with ether, the organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, concentrated and purified according to silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to obtain 52 g of the intended product.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4=C5SC=[CH:28][C:25]5=[N:26][CH:27]=[C:22]4[N:21]=[C:20]3[C@H:31]([OH:33])[CH3:32])[CH2:15][O:14]2)(=O)=O)=CC=1.[C-:34]#[N:35].[Na+].[CH3:37][S:38]([CH3:40])=O>CO>[OH:33][C@@H:31]([C:20]1[N:19]([C@@H:16]2[CH2:15][O:14][C@@H:13]([CH2:12][C:34]#[N:35])[CH2:18][CH2:17]2)[C:23]2=[C:40]3[S:38][CH:37]=[CH:28][C:25]3=[N:26][CH:27]=[C:22]2[N:21]=1)[CH3:32]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](n3c([C@@H](C)O)nc4cnc5ccsc5c43)CO2)cc1
Reactant: CS(C)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)methyl 4-methylbenzenesulfonate (from 1st peak of previous step, 27 mg, 0.055 mmol) and sodium cyanide (4.5 mg, 0.092 mmol) in dimethyl sulfoxide (0.4 mL) was stirred at 50° C. for 4 h. After cooling, the mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (14.5 mg, 76%). LCMS calculated for C17H19N4O2S (M+H)+: m/z=343.1. Found: 343.0. 1H NMR (DMSO-d6, 500 MHz) δ 9.51 (1H, s), 8.45 (1H, d, J=5.5 Hz), 7.97 (1H, d, J=5.5 Hz), 5.31 (1H, m), 5.20 (1H, m), 4.31 (1H, m), 4.23 (1H, m), 4.02 (1H, m), 2.96 (1H, dd, J=17.0 and 4.5 Hz), 2.85 (1H, dd, J=17.0 and 4.5 Hz), 2.66 (1H, m), 2.26 (1H, m), 2.09 (1H, m), 1.73 (1H, m), 1.69 (3H, d, J=6.5 Hz) ppm.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(O)C(N)(CO)CO>C(Cl)Cl>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:3]2[CH2:2][CH2:1][C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[NH:7][C:6]=3[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (Example 1, 52 mg, 0.2 mmol) in DCM was added 4-fluorobenzoyl chloride (36 μL, 0.2 mmol) and TEA (56 μL, 0.4 mmol) and the mixture was shaken overnight at 20° C. Trisamine resin (50 mg) was added and the suspension was shaken for 2 hours at 20° C. The resin was removed by filtration through a Florisil® cartridge. Evaporation of solvent gave a crude product, which was purified by trituration with methanol to give the title compound (28 mg); 1H-NMR (CDCl3): δ 10.31 (1H, br s), 7.79 (1H, s), 7.41 (2H, m), 7.36 (1H, d), 6.90-7.04 (5H, m), 3.99-4.06 (4H, m), 3.06 (2H, t), 1.02 (3H, t); MS (ES): 379 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27](Br)=[CH:26][N:25]=[C:24]([N:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH3:30])[N:23]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][Si](C(C)(C)C)(C)C)=[CH:9][CH:8]=1)[CH3:2].[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([NH:21][C:22]1[C:27]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[F:38])=[CH:26][N:25]=[C:24]([N:29]([CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH3:30])[N:23]=1)[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1Br)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Nc1nc(N(C)C2CCCCC2)ncc1-c1ccccc1F)c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A suspension of (R)-3-(5-bromo-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-(tert-butyldimethylsiloxy)phenyl)propanoic acid ethyl ester (1.0 eq), 2-fluorophenylboronic acid (3.0 eq), K3PO4 (3.0 eq) and Pd(PPh3)4 (0.03 eq) in DMF under nitrogen was stirred at 90° C. for 5 h. The DMF was evaporated, the residue was dissolved in EtOAc, and the resulting solution was washed successively with 0.5 M citric acid, sat. NaHCO3 and sat. NaCl. The EtOAc extracts were treated with MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica gel using 6:4 hexanes/EtOAc to give (R)-3-(5-(2-fluorophenyl)-2-(N-cyclohexyl-N-methylamino)pyrimidin-4-ylamino)-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[N:10]([NH:19][C:20](=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1>CO.[Pd]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:20]([NH:19][N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:18])=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Agent: [Pd]
Solvent: CO
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccccc2)c2ccccc2c1=O
Reaction time: 8 h
Yield: 100 %

Procedure:
A suspension of the product of Example 3 (29.9 mg, 0.064 mmol) and 10% Pd/C (catalytic amount) in MeOH (1 mL) was stirred under H2 (1 atm) overnight, filtered though Celite, and concentrated to give the title compound (24.9 mg, 0.064 mmol) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 11.70 (s, 1H), 8.45-8.35 (m, 1H), 8.01-7.90 (m, 2H), 7.76-7.68 (m, 1H), 7.58 (s, 5H), 7.40 (s, 4H), 3.70 (s, 2H); MS (ESI−) M/Z 388 (M−H)−.