Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14]/[CH:15]=[C:16](\[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:33]CCl>C(O)C.CC(C)=O>[ClH:33].[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1/[C:16](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:15]\[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCO/C=C(/c2ccccc2)c2ccccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: Cc1ccccc1/C(=C\OCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
Z-(R)-1-[2-[[2-(2-Methylphenyl)-2-phenylethenyl]oxy]ethyl]-3-piperidine carboxylic acid ethyl ester (2.0 g, 0.0051 mol) (prepared as described in Method A) was dissolved in ethanol (8 ml) and 12N sodium hydroxide solution (1.3 ml) was introduced. After stirring the solution at room temperature for 2 h, 37% hydrochloric acid (ca. 1.8 ml) was added with cooling, followed by dichloromethane (300 ml) and the mixture was dried (Na2SO4). Filtration and evaporation of the filtrate gave a residue, which was co-evaporated with acetone. The solid product was triturated with ethyl acetate, collected by filtration and dried in vacuo to give the title compound (0.70 g, 34%), m.p. 206°-211° C.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:9])[CH2:6][CH2:7][CH3:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1/[CH:19]=[CH:20]/[CH:21]=[C:22](\[O:27][CH3:28])/[C:23](OC)=[O:24]>C1(C)C=CC=CC=1.ClCCl>[CH2:5]([NH:9][C:23](=[O:24])/[C:22](/[O:27][CH3:28])=[CH:21]/[CH:20]=[CH:19]/[C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Reactant: CCCCN
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCNC(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
A 2M solution of trimethylaluminium in toluene (0.4 ml) was added at room temperature under nitrogen to a solution of butylamine (0.04 ml, 0.39 mmol) in dichloromethane (10 ml). Stirring was continued for 30 minutes and methyl (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4-pentadienoate (0.1 g, 0.39 mmol) was added. The solution was refluxed for 5 hours; after cooling to 10° C., the reaction was quenched with 10% HCl and the separated organic layer was washed with a saturated solution of NaHCO3 and water, dried over Na2SO4 and evaporated under vacuum. The solid residue was triturated with isopropyl ether, to give 55 mg (47.3%) of the title compound as a solid, m.p.=185-186° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35](O)=[O:36])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1.Cl.[CH2:39]([O:46][NH2:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([NH:47][O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:36])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: NOCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Product: O=C(/C=C/c1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1)NOCc1ccccc1
Yield: 72.9 %

Procedure:
The title compound was prepared as described in Example 34.B using (2E)-3-(4-{[2-(4-fluorophenyl)-6-(phenylmethoxy)(1,2,3,4-tetrahydroisoquinolyl)]methyl}phenyl)prop-2-enoic acid (0.365 g, 0.74 mmol), O-benzylhydroxylamine hydrochloride (0.16 g, 1.0 mmol), and 4-(N,N-dimethylamino)pyridine (0.121 g, 1.0 mmol) to provide the title compound (0.323 g, 73% yield): 1H NMR (CDCl3) 8.00 (br, 1H), 7.70 (d, 1H), 7.30-7.42 (m, 12H), 7.01 (d, 2H), 2.92 (m, 2H), 6.66-6.82 (m, 6H), 5.03 (s, 2H), 4.97 (s, 2H), 4.75 (t, 1H), 3.56 (m, 1H), 3.47 (m, 1H), 3.17 (dd, 1H), 2.88-3.00 (m, 2H), 2.66 (dt, 1H); ES-MS m/z 599 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:14])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 4-formylcinnamic acid (7.04 g, 40 mmole), anhydrous potassium carbonate (16.5 g, 120 mmole) and methyl iodide (8.5 g, 60 mmole) in dry N,N-dimethylformamide (50 ml) was stirred overnight at room temperature and the solvent evaporated in vacuo. The product was partitioned between ether and water and the organic phase washed with brine and dried (MgSO4). Evaporation gave 7.32 g (97%) of the title ester of mp (aqueous methanol) 83°-85° C., νmax (mull) 1723, 1683, 1635 cm-1, δ(CDCl3) 3.83 (3H, s, CH3), 6.52 (1H, d, J15 Hz, C=CHCO2), 7.75 (1H, d, J 15 Hz, ArCH=C), 7.79 (4H, ABq, J 6 Hz, Δν16.5 Hz, arom), 10.08 (1H, s, CHO).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4].N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(Cl)Cl>>[C:26]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(1-hydroxypropan-2-yl)-6-methyl-5-nitroisoquinolin-1(2H)-one (100.0 mg, 0.0003813 mol), pyridine (0.062 mL, 0.00076 mol), acetic anhydride (0.0432 mL, 0.000458 mol) and methylene chloride (5 mL, 0.08 mol) was stirred at room temperature overnight. The reaction went to completion and the solvent was removed under reduced pressure, and the resulting product was dried in vacuum (yellow oil) and was used in the next reaction without any purification. MS m/z=305.4 (M+H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=2)[N:3]=1.Cl.[CH3:24][NH2:25].C([O-])([O-])=O.[Na+].[Na+]>CC(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[N:3]=[C:2]([NH:25][CH3:24])[N:11]=2)=[CH:15][CH:16]=1
Reactant: CN
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc(C)cc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CNc1nc(N(C)c2ccc(OC)cc2)c2cc(C)ccc2n1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
A solution of (2-chloro-6-methyl-quinazolin-4-yl)-(4-methoxyphenyl)-methyl-amine (62.9 mg, 0.20 mmol), methylamine hydrochloride (145.8 mg, 2.2 mmol) and Na2CO3 (234.5 mg, 2.2 mmol) in i-PrOH (2 mL) was heated to 100° C. overnight. After cooling to room temperature the reaction mixture was concentrated onto SiO2 and purified by gradient MPLC (SiO2, 0 to 20% MeOH/CH2Cl2 with 0.1% NH4OH, 20 min). 20.3 mg (33%) of the title compound was obtained: 1H NMR (DMSO-d6, 90° C.) δ 7.93 (br s, 1 H), 7.38-7.52 (m, 2 H), 7.33 (d, 2 H), 7.08 (d, 2 H), 6.39 (s, 1 H), 3.83 (s, 3 H), 3.62 (s, 3 H), 3.06 (s, 3 H), 1.96 (s, 3 H). HRMS (ES) calcd for C18H21N4O [(M+H)] 309.1710, found 309.1714.
Reaction SMILES: CN(C)C=O.[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:36]/[OH:37])/[C:32]([O:34][CH3:35])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46]>O>[C:6]([NH:25][C:26]1[S:27][CH:28]=[C:29](/[C:31](=[N:36]/[O:37][CH2:46][CH:45]=[CH2:44])/[C:32]([O:34][CH3:35])=[O:33])[N:30]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CCBr
Reactant: COC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO/N=C(\C(=O)OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 91.1 %

Procedure:
To 70.5 ml of N,N-dimethylformamide are added 7.05 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-hydroxyiminoacetate and 3.3 g of potassium carbonate. Then, under ice-cooling and stirring 2.12 g of allyl bromide is added dropwise over a period of 5 minutes. The mixture is further stirred under ice-cooling for 4 hours. To this reaction mixture are added 1.65 g of potassium carbonate and 1.06 g of allyl bromide, and the mixture is stirred for an additional 4 hours. The reaction mixture is diluted with 150 ml of water and extracted three times with 100 ml portions of ether. The ether extract is washed twice with 100 ml portios of aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off and the residue is purified by column chromatography [silica gel: 300 g; eluent: hexane-ethyl acetate (1:1)] and crystallized from ether-hexane to give 7.0 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-allyloxyiminoacetate, m.p. 115°- 116° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[N:14]1[NH:15][N:16]=[N:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]2[N:14]=[N:15][NH:16][N:17]=2)=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2nn[nH]n2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(-c3nn[nH]n3)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2,4-dimethylphenyl)(2-methylpropyl)amine (100 mg, 0.564 mmol) in pyridine (2 mL) was added 4-(2H-tetrazol-5-yl)benzene-1-sulfonyl chloride (138 mg, 0.564 mmol) and the mixture stirred at 20° C. for 30 minutes, then stood at room temperature, in air, for 16 hours. The crude was then purified by flash silica (Si) chromatography (using a 25-100% ethyl acetate-cyclohexane gradient) to give a colourless gum. This was further dried under a stream of nitrogen, then under vacuum for 3 hours, to give the final product, 104.87 mg. LCMS (M+1) 386, RT 1.22 mins.
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37])[CH:24]([CH3:26])[CH3:25]>>[C:1]([O:36][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:28]1=[O:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CN1C(=O)C(=O)c2ccccc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate from 1-isobutylindoline-2,3-dione. 1H-NMR δ 8.10 (d, 2H), 7.59 (t, 1H), 7.46 (m, 3H), 7.34 (m, 1H), 7.05 (t, 1H), 6.89 (d, 1H), 6.18 (s, 1H), 3.52 (m, 2H), 2.18 (m, 1H), 1.01 (dd, 6H).
Reaction SMILES: [OH:1][B:2]1[C@@H:7]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][N:10]=2)[CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:4]=2[O:3]1.[C:22](=[O:30])([O:26][CH:27]([CH3:29])[CH3:28])[O:23][CH2:24]Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:1][B:2]1[C@@H:7]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][N:10]=2)[CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([O:21][CH2:24][O:23][C:22]([O:26][CH:27]([CH3:29])[CH3:28])=[O:30])=[O:20])[C:4]=2[O:3]1
Reactant: CC(C)OC(=O)OCCl
Reactant: Cn1cnnc1S[C@H]1Cc2cccc(C(=O)O)c2OB1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)OCOC(=O)c1cccc2c1OB(O)[C@@H](Sc1nncn1C)C2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To the solution of acid 15 (0.5 mmol) in DMF (5 mL) was added chloromethyl isopropyl carbonate (1 mmol), followed by K2CO3 (0.75 mmol). The resulting mixture was stirred at 50° C. for 18 hours and brought to room temperature and concentrated. The residue was purified by purified by prep-HPLC (C18, acetonitrile and water as mobile phases, 0.1% formic acid) to obtain the titled compound.
Reaction SMILES: S([O-])(=O)(=O)C.[CH3:6][C:7]1[O:11][N:10]=[C:9]([CH2:12]OS(C)(=O)=O)[CH:8]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:38]=[C:26]2[N:27]=[C:28]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[N:29]=[C:30]([NH2:31])[N:25]2[N:24]=1.CCN(CC)CC>CC#N>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[N:38]=[C:26]2[N:27]=[C:28]([N:32]3[CH2:37][CH2:36][N:35]([CH2:12][C:9]4[CH:8]=[C:7]([CH3:6])[O:11][N:10]=4)[CH2:34][CH2:33]3)[N:29]=[C:30]([NH2:31])[N:25]2[N:24]=1
Reactant: Cc1cc(COS(C)(=O)=O)no1
Reactant: Nc1nc(N2CCNCC2)nc2nc(-c3ccco3)nn12
Agent: CS(=O)(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN2CCN(c3nc(N)n4nc(-c5ccco5)nc4n3)CC2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The mesylate derivative from subpart (a) above (0.28 mmol) was added to a solution of 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.14 mmol; see Example 1(a) above) and Et3N (0.3 mmol) in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temperature for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][NH:22][CH:23]=4)[CH:18]=[C:13]3[C:12]([C:24]3[N:29]=[C:28]([NH:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33][CH2:32]4)[CH:27]=[N:26][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[NH:21]1[CH:20]=[C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:24]4[N:29]=[C:28]([NH:30][C@H:31]5[CH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][CH2:36]5)[CH:27]=[N:26][CH:25]=4)=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)[CH:23]=[N:22]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cncc(N[C@H]3CC[C@H](O)CC3)n2)c2cc(-c3cn[nH]c3)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O[C@H]1CC[C@H](Nc2cncc(-c3c[nH]c4ncc(-c5cn[nH]c5)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of trans-4-({6-[1-(phenylsulfonyl)-5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl)amino}cyclohexanol (0.63 g, 0.12 mmol) in MeOH (1.3 mL) was added potassium carbonate (0.051 g, (0.37 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with MeOH (10 mL) and CH2Cl2 (10 mL), silica gel was added and concentrated to a crude residue. The residue was purified by silica gel chromatography (MeOH/CH2Cl2 gradient) to afford trans-4-({6-[5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl)amino}cyclohexanol as a yellow solid. 1H NMR (600 MHz, DMSO-D6) δ 12.95 (s, 1H); 11.99 (s, 1H); 8.75 (s, 1H); 8.53 (s, 1H); 8.19 (s, 1H); 8.14 (d, 1H); 7.92 (s, 1H); 7.64 (s, 1H); 6.79 (d, 1H); 4.49 (d, 1H); 3.79 (br s, 1H); 3.43 (br s, 1H); 1.83 (br s, 2H); 1.31 (br s, 2H); 1.26 (q, 4H). LRMS (ESI) calculated for C20H21N7O [M+H]+, 376.2; found 376.1.
Reaction SMILES: ClCCC[O:5][P:6]1[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1.[CH2:12](O)[CH:13]=[CH2:14]>>[CH2:14]([P:6]1(=[O:5])[CH2:10][CH:9]=[C:8]([CH3:11])[CH2:7]1)[CH:13]=[CH2:12]
Reactant: C=CCO
Reactant: CC1=CCP(OCCCCl)C1
Product: C=CCP1(=O)CC=C(C)C1

Procedure:
To 8 g. (0.0448 mole) of 1-(chloropropoxy)-3-methyl-3-phospholene there was added 2.9 g. (0.05 mole) of allyl alcohol. The mixture was allowed to stand at room temperature and then distilled under reduced pressure to remove volatile material. There was thus obtained 1-allyl-3-methyl-3-phospholene-1-oxide.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1)[CH:2]=[CH2:3].C([Li])(C)(C)C.[CH2:17]([N:24]([CH2:37][C:38]1[CH:49]=[CH:48][C:41]([C:42](N(OC)C)=[O:43])=[CH:40][CH:39]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:26]=1[CH3:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[C:42]([C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:25]2[C:26]([CH3:36])=[C:27]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:28]=[CH:29][CH:30]=2)=[CH:49][CH:48]=1)=[O:43])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(Br)c1
Reactant: CON(C)C(=O)c1ccc(CN(Cc2ccccc2)c2cccc(NS(C)(=O)=O)c2C)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=CCOc1cccc(C(=O)c2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
The product from Example 88C (0.983 g, 3.80 mmoles) in anhydrous THF (10 mL) at −78° C. was treated dropwise with 1.7 M t-butyllithium (4.46 mL, 7.59 mmoles). Reaction stirred 30 minutes at −78° C. and was then treated with the product from Example 88B (1.00 g, 1.90 mmoles. Reaction stirred 15 minutes at −78° C. and then allowed to warm to 0° C. Reaction quenched with saturated NH4Cl and warmed to room temperature. The mixture was diluted with ethyl acetate, washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on a pre-packed Biotage silica gel column (30% ethyl acetate:hexanes) to provide the title compound (0.369 g, 36%). MS (ESI−) m/z 539 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:19][C:20](=[O:23])[NH:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[N:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.15 mole of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 0.15 mole of tert-butylcarbazate in 250 ml of hexane is stirred for 18 h at RT. The precipitate is filtered off and dried under vacuum. M.p. 172-174° C.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[C:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[CH:39][C:38]=1[C:51]1[N:60]=[CH:59][C:58]2[CH2:57][CH2:56][C:55]3[N:61]=[C:62]([NH:64][C:65](=[O:67])[CH3:66])[S:63][C:54]=3[C:53]=2[N:52]=1>ClCCl>[C:1]([N:48]1[CH2:47][CH2:46][CH:45]([C:44]#[C:43][C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[C:38]([C:51]3[N:60]=[CH:59][C:58]4[CH2:57][CH2:56][C:55]5[N:61]=[C:62]([NH:64][C:65](=[O:67])[CH3:66])[S:63][C:54]=5[C:53]=4[N:52]=3)[CH:39]=2)[CH2:50][CH2:49]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(C(C)=O)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7 μl acetic acid and 50 mg (0.16 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) are placed in 5 mL dichloromethane, combined with 32 μl diisopropylethylamine and stirred for 0.5 hours at ambient temperature. 60 mg (0.13 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydro-thiazolo[4,5-h]quinazolin-2-yl]-acetamide (Example 155) are added, then the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is extracted with potassium carbonate solution and dichloromethane. The organic phase is dried and evaporated to dryness. The residue is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18]([NH2:20])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[CH:8]=[C:7]2[C:18](=[S:30])[NH2:20]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=S)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
A mixture of 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid amide (1.8 g, 6.0 mmol), Lawesson's reagent (4.85 g, 12.0 mmol), toluene (150 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained reside was purified by column chromatography eluting with 20-50% (v/v) ethyl acetate in n-heptane to afford 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carbothioic acid amide (1.4 g, 4.5 mmol).
Reaction SMILES: O=[C:2]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]#[N:5].O.[NH2:16][NH2:17]>CCO>[C:9]1([C@@H:7]2[CH2:8][C@H:6]2[C:2]2[CH:3]=[C:4]([NH2:5])[NH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CCC(=O)[C@@H]1C[C@H]1c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cc([C@@H]2C[C@H]2c2ccccc2)n[nH]1
Temperature: 80 °C
Reaction time: 6 h
Yield: 127.5 %

Procedure:
To a stirred solution of 39 (28.5 g, 153.87 mmol, 1.00 equiv) in EtOH (300 mL) under N2 was added 85% hydrazine hydrate (5.7 g, 100 mmol, 0.65 equiv), and the reaction mixture was stirred at 80° C. for 6 h. The reaction was cooled to RT, and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH gradient (1 to 5% MeOH) to afford 25.4 g (83%) of trans-3-(2-phenylcyclopropyl)-1H-pyrazol-5-amine (41) as a light yellow oil: 1H NMR (400 MHz, DMSO-d6): δ 7.30-7.10 (m, 5H), 5.15 (s, 1H), 4.90-4.20 (br s, 2H), 2.10-2.07 (m, 1H), 2.00-1.95 (m, 1H), 1.35-1.31 (m, 2H), 1H not seen; MS (ESI+) m/z=200 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14](Cl)[N:13]=[CH:12][N:11]=1>O1CCCC1>[CH3:7][O:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:13]=[CH:12][N:11]=1
Reactant: COCc1ncnc(Cl)c1C
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: COCc1ncnc(N2CCCCC2)c1C
Reaction time: 8 h

Procedure:
Piperidine (15 ml) in tetrahydrofuran (40 ml) was added dropwise to a solution of 4-methoxymethyl-5-methyl-6-chloropyrimidine (5 g) in tetrahydrofuran (40 ml). The mixture was heated under reflux for 7 hours and then allowed to stand overnight at room temperature. It was filtered, stripped, and water added to the residual oil. The pH was lowered to 7.5 (HCl) and extracted with chloroform. Extracts were dried (K2CO3) and stripped to give 4-methoxymethyl-5-methyl-6-piperidinopyrimidine, 6.08 g, as an oil, which solidified on cooling to 5° (m.p. 45°-47°). It was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[N:7]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[N:6]=[C:5]2[CH:20]=[CH2:21]>C(O)C.O1CCCC1.[C].[Pd]>[CH2:20]([C:5]1[C:4]2[C:8](=[CH:9][C:10]([NH2:11])=[C:2]([CH3:1])[CH:3]=2)[N:7]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:6]=1)[CH3:21]
Reactant: C=Cc1nn(C2CCCCO2)c2cc([N+](=O)[O-])c(C)cc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1nn(C2CCCCO2)c2cc(N)c(C)cc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
The compound (3.04 g, 10.6 mmol) of step A was dissolved in an ethanol (100 ml)-tetrahydrofuran (10 ml) mixed solvent, and the mixture was stirred at room temperature. Then, 10% palladium carbon (containing water) (3.20 g) was added, and the mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The insoluble material was filtered off through celite, and the obtained solution was concentrated under reduced pressure to give the title compound (2.69 g, yield 98%) as a pale-yellow oil.