Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[CH3:18])[CH2:13][CH3:14]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCCC1(C(=O)OCC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 2-methyl-benzoyl chloride (5.95 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 9.61 g of yellow liquid. MS: m/e 319(M+′+1), 318(M+′), 273, 259, 199, 183, 153, 119(base), 91, 77.
Reaction SMILES: [H][H].[O:3]=[C:4]1[CH:9]([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21]C=O)[N:12]=[C:11]2[CH3:24])[CH2:8][CH2:7][C:6](=[O:25])[NH:5]1>C(O)=O>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:10]([CH:9]1[CH2:8][CH2:7][C:6](=[O:25])[NH:5][C:4]1=[O:3])[C:11]([CH3:24])=[N:12]2
Reactant: [H][H]
Reactant: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O
Solvent: O=CO
Product: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In certain embodiments, when the hydrogen donor is formic acid, the transfer hydrogenation further comprises the step of hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione as described herein elsewhere.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(Br)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(Br)nc1C
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of 6-bromo-2-methyl-pyridin-3-ol (4.06 g, 21.59 mmol), methyl iodide (1.61 mL, 25.91 mmol), potassium carbonate (5.97 g, 43.18 mmol) and acetonitrile (183.0 mL) was heated at reflux for 17 hours. The mixture was cooled to room temperature, filtered through a plug of celite and the solvent was evaporated under reduced pressure. Water (50 mL) and ethyl acetate (100 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography utilizing a gradient of 0-20% ethyl acetate in hexane to yield 6-bromo-3-methoxy-2-methyl-pyridine (3.18 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO) δ 7.42 (d, J=8.6 Hz, 1H), 7.33 (d, J=8.6 Hz, 1H), 3.82 (s, 3H), 2.32 (s, 3H). ESI-MS m/z calc. 201.0, found 202.1 (M+1)+; Retention time: 1.19 minutes (3 min run).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[C@@H:16]([OH:24])[C@H:15]2[OH:25])=[C:7]([NH:26][CH2:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:6]=1)=O.[CH2:41]([NH2:44])[CH2:42][NH2:43]>>[NH2:43][CH2:42][CH2:41][NH:44][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[C@@H:16]([OH:24])[C@H:15]2[OH:25])=[C:7]([NH:26][CH2:27][CH:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:6]=1)=[O:2]
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)[C@H](O)[C@@H]1O
Reactant: NCCN
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid methyl ester (62 mg, 1.0 mmol) is dissolved in ethylene diamine (3.4 ml, 51 mmol) and the solution is stirred at 105° C. The reaction is shown to be complete by LCMS after 45 minutes. The reaction mixture is concentrated in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water). MS (ES+) m/e 573.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:9]1[N:10](C(OC(C)(C)C)=O)[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:8])[CH3:7])=[O:5])[CH3:2]>ClCCl.C(O)(C(F)(F)F)=O>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:9]1[C:6]([CH3:7])([CH3:8])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C(C)(C)c1cc2ccccc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.2 %

Procedure:
tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-yl)-1H-indole-1-carboxylate (22.9 g, 69.1 mmol) was dissolved in dichloromethane (200 mL) before TFA (70 mL) was added. The mixture was stirred for 5 h at room temperature. The mixture was evaporated to dryness, taken up in dichloromethane and washed with saturated sodium bicarbonate solution, water, and brine. The product was purified by column chromatography on silica gel (0-20% EtOAc in hexane) to give ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (12.5 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 63.1 %

Procedure:
A solution of 4(2-bromo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (81.5 g 0.279 mol) in dry tetrahydrofuran (1000 ml) under nitrogen at 20° was treated portionwise, over 30 min, with potassium tert-butoxide (63.2 g 0.563 mol). The mixture was stirred at 25° for 3 h and partitioned between saturated aqueous ammonium chloride (1000 ml) and diethyl ether (500 ml). The aqueous phase was extracted with diethyl ether (4×500 ml) and the combined, dried (MgSO4) extracts were evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (Merck 9385) eluant cyclohexane: diethyl ether (19:1) to give the title compound as an orange oil (37.1 g, 0.176 mol, 63%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N)C1=O
Product: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.40 g of t-butyl α-[6-amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] was N-alkylated using 0.64 g of ethyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]Cl)[CH:15]=1.[H-].[Na+]>>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][N:1]2[CH2:6][CH2:5][S:4](=[O:8])(=[O:7])[CH2:3][CH2:2]2)[CH:13]=[N:12][CH:11]=1
Reactant: O=S1(=O)CCNCC1
Reactant: ClCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: O=S1(=O)CCN(Cc2cncc(Br)c2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediates A-12 [B], thiomorpholine 1,1-dioxide was reacted with 3-bromo-5-chloromethyl-pyridine (intermediate A-12 [A]) in the presence of NaH to give the title compound as a white solid. MS: 304.9, 307.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[C:2]1([CH:1]=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[Se]=O
Reactant: Cc1nccc2ccccc12
Solvent: C1COCCO1
Product: O=Cc1nccc2ccccc12
Temperature: 25 °C
Yield: 76.4 %

Procedure:
In 1,4-dioxane (20 ml) was dissolved 1-methylisoquinoline (300 mg, 2.10 mmol). To the resulting solution was added selenium dioxide (323 mg, 2.91 mmol), followed by heating under reflux for 1.5 hours under a nitrogen gas stream. After cooling to room temperature, the reaction mixture was filtered through Celite. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (5:1, v/v) eluate fractions, 1-isoquinolinecarbaldehyde (252 mg, 77%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([I:24])=[CH:21][CH:22]=3)[C:17](=[O:25])[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15]2)[CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[CH2:29]([O:28][C:26]([C:16]1[C:17](=[O:25])[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([I:24])[CH:19]=2)[N:14]([CH2:13][C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:15]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)c1cn(C[C@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C[C@@H]2CCNC2)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude (R)-ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 95, ˜4.4 mmol) was dissolved in 1,4-dioxane (20 mL) and 4.0M hydrogen chloride in 1,4-dioxane (20 mL) was added. The reaction mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo. The solid was then dried in a vacuum oven at 40° C. for 18 h to give 2.3 g (quant. yield) of (R)-ethyl-6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride as a yellow solid.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]([C:26](N(OC)C)=[O:27])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][Mg]Br>O1CCCC1>[Si:1]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:16]([C:26](=[O:27])[CH3:32])=[CH:17][C:18]([Cl:25])=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloro-N-methoxy-N-methylquinoline-7-carboxamide (312 mg, 0.672 mmol) in tetrahydrofuran (0.9 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (2.9 mL, 4.0 mmol). The reaction was stirred at room temperature overnight, then quenched with sat. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and then concentrated to dryness under reduced pressure to afford the desired product (0.275 g, 98%). LCMS calculated for C22H32ClN2O2Si (M+H)+: m/z=419.2; Found: 419.1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[N:12]=[C:13]([NH2:25])[C:14]2[N:15]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:16]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[N:12]=[C:13]([NH2:25])[C:14]2[N:15]([N:17]=[C:18]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC#Cc1cn2nc(-c3ccco3)nc2c(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-prop-2-ynyl]-carbamic acid tert-butyl ester (100 mg, 0.28 mmol; see Ex. 41 below which was prepared according to Example 3 above) in CH2Cl2 (3 mL) was added trifluoroacetic acid (107 uL, 1.4 mmol). The reaction was stirred at room temperature for 2 hours. The solvent and trifluoroacetic acid was removed to yield 6-(3-amino-prop-1-ynyl)-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine as brown oil. The compound was used without further purification. MS: m/z=255 amu (M++H)
Reaction SMILES: [CH2:1]([N+:5]([O-:7])=[O:6])/[CH:2]=[N:3]\O.Cl.N[C:10]1[C:17]([F:18])=[C:16]([Cl:19])[C:15]([F:20])=[CH:14][C:11]=1[CH:12]=O>C(O)C>[Cl:19][C:16]1[C:17]([F:18])=[C:10]2[C:11]([CH:12]=[C:1]([N+:5]([O-:7])=[O:6])[CH:2]=[N:3]2)=[CH:14][C:15]=1[F:20]
Reactant: Nc1c(C=O)cc(F)c(Cl)c1F
Reactant: O=[N+]([O-])C/C=N\O
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1cnc2c(F)c(Cl)c(F)cc2c1
Temperature: 35 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
17.4 g of methazonic acid and 60 cm3 of a 37% aqueous hydrochloric acid solution were rapidly added, with stirring, to a solution of 8.7 g of 2-amino-4-chloro-3,5-difluorobenzaldehyde in 300 cm3 of ethanol, while the mixture was maintained at a temperature in the region of 35° C. The mixture was stirred for 16 hours at a temperature in the region of 20° C. The precipitate was dewatered and washed 3 times with 25 cm3 of diethyl ether. 8.1 g of 7-chloro-6,8-difluoro-3-nitroquinoline was obtained in the form of an orange-colored solid, which melted at 174° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=4)(=[O:36])=[O:35])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][NH:21][C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[O:48]1[CH2:51][C:50](=O)[CH2:49]1>C(Cl)Cl.CCOC(C)=O>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:47])=[C:8]([N:10]2[CH2:46][CH2:45][C:13]3[N:14]=[C:15]([C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[C:27]([CH3:44])=[CH:28][N:29]5[S:34]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=4)(=[O:35])=[O:36])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([CH:50]5[CH2:51][O:48][CH2:49]5)[C@H:20]([CH3:24])[CH2:19]4)[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Reactant: O=C1COC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(C7COC7)[C@H](C)C6)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (53 mg, 0.082 mmol), oxetan-3-one (17.6 mg, 0.245 mmol) and Na(AcO)3BH (51.9 mg, 0.245 mmol) in DCM (3 mL) was stirred at rt for 3 h. At that point starting material remained so additional oxetan-3-one (17.7 mg, 0.245 mmol) and Na(AcO)3BH (51.9 mg, 0.245 mmol) were added and the reaction stirred for 16 h. The mixture was then diluted with EtOAc, washed with sat NaHCO3 and brine. The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified by FCC (5-65% EtOAc/heptane) to provide (R)-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 705.5 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH:9]=[CH:10][CH3:11].[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:14][CH2:13]1>CN(C)C=O>[CH2:8]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[CH:24]3)=[O:20])[CH2:14][CH2:13]1)[CH:9]=[CH:10][CH3:11]
Reactant: O=C(NC1CCNCC1)c1ccc2[nH]ncc2c1
Reactant: CC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCN1CCC(NC(=O)c2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.1 %

Procedure:
Potassium carbonate (55.0 mg, 0.398 mmol) and 1-chloro-2-butene (17.8 mg, 0.197 mmol) were added to a solution of the N-(4-piperidinyl)-1H-indazole-5-carboxamide (40.0 mg, 0.164 mmol) obtained in Example 58 in N,N-dimethylformamide (1.2 ml), and the resulting mixture was stirred for 20 hours while being maintained at room temperature. The reaction solution was filtered and the filtrate was concentrated to dryness. The resulting crude product residue was purified by a silica gel column chromatography (eluent: chloroform/methanol/aqueous ammonia=20/1/0.1) to obtain N-[1-(but-2-enyl)piperidin-4-yl]-1H-indazole-5-carboxamide (26 mg, 54%).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15](=[O:34])[C@H:16]([CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[C:27]([Cl:33])[CH:26]=1)[NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20].[C:35]1([C:41]2[O:42][C:43]3[C:49]([CH2:50]O)=[CH:48][CH:47]=[CH:46][C:44]=3[N:45]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15](=[O:34])[C@H:16]([CH2:24][C:25]1[CH:26]=[C:27]([Cl:33])[C:28]([O:32][CH2:50][C:49]2[C:43]3[O:42][C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:45][C:44]=3[CH:46]=[CH:47][CH:48]=2)=[C:29]([Cl:31])[CH:30]=1)[NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(O)c(Cl)c1)NC(=O)C(F)(F)F
Reactant: OCc1cccc2nc(-c3ccccc3)oc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(Cl)c(OCc2cccc3nc(-c4ccccc4)oc23)c(Cl)c1)NC(=O)C(F)(F)F
Reaction time: 60 h
Yield: 81.6 %

Procedure:
Diethylazodicarboxylate (40% toluene solution 0.63 ml) was added dropwise to a solution of 3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (252 mg, 0.7 mmol), [(2-phenyl)-benzoxazol-7-yl]methanol (193 mg, 0.857 mmol) and triphenylphosphine (374 mg, 1.43 mmol) in tetrahydrofuran (3 ml) under argon atmosphere at 5° C., and the mixture was stirred at the same temperature for 60 hrs. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4) to give 3,5-dichloro-N-trifluoroacetyl-O-[(2-phenyl)-benzoxazol-7-yl]methyl-L-tyrosine methyl ester (324 mg, 82%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20]CC)=[O:19]>>[O:23]=[C:16]1[C:17]([C:18]([OH:20])=[O:19])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:1]1
Reactant: Nc1ccccc1C(=O)c1ccccn1
Reactant: CCOC(=O)CC(=O)OCC
Product: O=C(O)c1c(-c2ccccn2)c2ccccc2[nH]c1=O
Temperature: 180 °C

Procedure:
A mixture of 2-(2-aminobenzoyl)pyridine (4.36 g), diethyl malonate (3.92 ml) and 1,9-diazabicyclo[5.4.0]-7-undecene(0.5 ml) was heated for 3 hours at 180° C. The reaction mixture was cooled to give ethyl ester of 1,2-dihydro-2-oxo-4-(2-pyridyl)-3-quinolinecarboxylic acid as crystals (6.1 g: unrefined). The crystalline product was dissolved in DMF (100 ml), to which sodium hydride (60% oily) (1.5 g) was added, and the mixture was stirred for one hour at room temperature. The mixture was cooled to 0° C., to which was added, while stirring, iodomethane (10 ml). The mixture was stirred for one hour at room temperature, which was then concentrated. To the concentrate was added ethyl acetate. The mixture was washed with water and dried. The solvent was then distilled off. The residue was purified by means of a silica-gel column chromatography (ethyl acetate) to give ethyl eater of 1,2-dihydro-1-methyl-2-oxo-4-(2-pyridyl)-3-quinoline carboxylic acid as pale yellow crystals (2.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([Cl:16])=[O:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)C=Cc1ccc(F)c(Br)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C=Cc1ccc(F)c(Br)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
3-(3-Bromo-4-fluoro-phenyl)-acrylic acid (3.3 g, 13.3 mmol) prepared in Step 1 was added to thionyl chloride (10.0 mL). The reaction mixture was stirred at 100° C. for 2 hours, concentrated under reduced pressure. The resulting residue was concentrated under reduced pressure three times, along with using toluene, to give 3.5 g of the titled compound as an unpurified dark brown liquid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[OH:20]O>C(O)(=O)C>[OH:10][C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2](=[O:1])[C:3]=1[S:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:20]
Reactant: Cc1ccc(CSC2=C(O)CC(C)(C)CC2=O)cc1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1ccc(CS(=O)C2=C(O)CC(C)(C)CC2=O)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3-hydroxy-5,5-dimethyl-2-(p-methylbenzylthio)-2-cyclohexen-1-one (10 g., 0.036 mole), 30 percent hydrogen peroxide (4.11 g., 0.0362 mole), and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 24 hours. The solution was poured into ice water, and the resulting pink solid was filtered and dried to give pure product (9.9 g., m.p. 89°-90.5°C.).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[CH:8]1([C:11]2[N:16]=[C:15]([C:17]([NH:19][C:20]3[CH:28]=[N:27][CH:26]=[CH:25][C:21]=3[C:22](O)=[O:23])=[O:18])[C:14]([NH:29][C:30]3[CH:31]=[N:32][CH:33]=[N:34][CH:35]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:22]([C:21]1[CH:25]=[CH:26][N:27]=[CH:28][C:20]=1[NH:19][C:17]([C:15]1[C:14]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:13][CH:12]=[C:11]([CH:8]2[CH2:10][CH2:9]2)[N:16]=1)=[O:18])=[O:23]
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: OCC1CCCN1
Product: O=C(Nc1cnccc1C(=O)N1CCCC1CO)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 29 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-hydroxymethylpyrrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound as off-white solid (29%).