Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7]O.C=O.[CH2:11]([NH:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCC>[CH2:11]([N:18]([CH2:7][O:4][CH3:1])[CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)CNCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CO
Agent: C=O
Agent: [K+]
Solvent: CCCCC
Product: COCN(Cc1ccccc1)C[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.50 g (0.018 mol) of potassium carbonate, 30.4 g (0.95 mol) of methanol and 15.0 g (0.50 mol) of paraformaldehyde are initially charged and cooled to 0° C. At this temperature, within 30 min, 96.7 g (0.50 mol) of benzyltrimethylsilanylmethylamine are metered in. The biphasic reaction mixture is stirred at 0° C. for a further 1 h and then warmed to room temperature within 20 min. Within 1 min, 190.9 g of pentane are metered in. The biphasic reaction mixture is separated and the upper, organic phase is dried azeotropically for 2 h. The organic phase is concentrated and then fractionally distilled. Yield 105.9 g (89%) of a colorless liquid. −b.p. 94° C./1 mbar. −1H NMR (C6D6): δ=0.09 (s, 9 H), 2.21 (s, 2 H), 3.00 (s, 3 H), 3.75 (s, 2 H), 3.87 (s, 2 H), 7.10-7.45 (m, 5 H).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:18]3[N:19]=[CH:20][NH:21][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>O1CCCC1.C(OCC)C>[C:23]1([CH2:22][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[CH:20][N:21]([CH2:34][O:33][CH2:31][CH3:32])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOCCl
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3[nH]cnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of N,N-bis(phenylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2 g, 5.49 mmole) in tetrahydrofuran (10 mL) was added to a suspension of sodium hydride (0.21 g, 6.58 mmole) in tetrahydrofuran (25 mL). After 30 minutes chloromethyl ethyl ether (0.61 mL, 6.58 mmole) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water, dried over magnesium sulfate, and then concentrated under vacuum to provide crude product as a brown oil. The oil was purified by column chromatography (silica gel eluting with 20-30% ethyl acetate in hexanes v/v) to provide 1.77 g of N,N-bis(phenylmethyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white/tan solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([CH2:17][O:18][C:19]2[CH:24]=[C:23]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:22]=[CH:21][C:20]=2[N+:26]([O-:28])=[O:27])[CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCC1CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
Diethyl malonate (9.8 g, 1.1 eq.) was added to a stirred suspension of sodium hydride (60% in mineral oil, 2.09 g) in 88 mL DMF over 15 min. at 0° C. under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. A solution of 2-cyclopropylmethoxy-4-fluoro-1-nitrobenzene (10 g, 1 eq.) in DMF (88 mL) was added drop wise at 0° C., and the reaction mixture was heated to 100° C. for 3 h. The reaction mixture was allowed to cool to room temperature, poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave 10.0 g of crude product which was purified by silica gel chromatography (hexane/EtOAc) gave 7.0 g of the desired product (42%)
Reaction SMILES: [C:1]([N:20]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH3:28][N:29]([CH:31]=[C:23]1[CH2:24][N:20]([C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21][C:22]1=[O:25])[CH3:30]
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Solvent: CN(C)C=O
Product: CN(C)C=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1=O
Temperature: 80 °C

Procedure:
A suspension of 1-tritylpyrrolidin-3-one (4.9 g) from Step A in anhydrous DMF (36.0 mL) was dissolved by heating at 80° C. under nitrogen for 10 min. The clear solution was treated with N,N-dimethylformamide dimethyl acetal (18.0 mL) and heated at 80° C. for 12 h. The resulting dark brown solution was evaporated under reduced pressure. The residue was chromatographed on a Biotage® system (silica gel, gradient from 50% to 100% ethyl acetate in hexanes) to yield the title compound. LC-MS=243.1 (M+1).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:19]2[C:28](=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:30][C:18]=2[C:17]=1[F:39])=O)(C)(C)C.Cl>CC(O)C>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:19]2[C:28](=[O:38])[NH:29][CH2:30][C:18]=2[C:17]=1[F:39]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)cn1
Agent: Cl
Solvent: CC(C)O
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 65 °C
Yield: 85.5 %

Procedure:
A suspension of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl-amino)-7-fluoro-4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (2.148 g, 3.94 mmol) in IPA (21 mL) was heated to 70° C. at which point 2M HCl aq (9.86 mL, 19.72 mmol) was added. The reaction mixture was heated at 65° C. for approximately 3 h, cooled in an ice water bath for 1 h, and then filtered. The solids were rinsed with cold IPA (15 mL) and then dried in a 50° C. vacuum oven overnight to give an HCL salt of the title compound as a light yellow solid (1.404 g, 3.37 mmol) having 1.5-2 eq of associated water (by 1H NMR). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=7.07 Hz, 2 H), 1.57-1.76 (m, 3 H), 1.76-2.04 (m, 3 H), 3.31 (s, 3 H), 3.67 (br s, 1 H), 3.90 (s, 3 H), 4.39 (d, J=2.53 Hz, 2 H), 4.41-4.60 (m, 1 H), 6.75 (d, J=6.57 Hz, 1 H), 7.96 (br s, 3 H), 8.22-8.31 (m, 1 H), 8.34 (s, 1 H), 8.84 (s, 1H). [M+H] calc'd for C17H21FN6O, 345; found 345.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)#[N:2].[CH3:11][O:12][CH:13]([O:21][CH3:22])[C:14](=[O:20])[CH2:15][C:16]([O:18][CH3:19])=[O:17].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[C:15]([C:14]([CH:13]([O:12][CH3:11])[O:21][CH3:22])=[O:20])[C:16]([O:18][CH3:19])=[O:17])#[N:2]
Reactant: COC(=O)CC(=O)C(OC)OC
Reactant: N#Cc1ccccc1C=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1ccccc1C#N)C(=O)C(OC)OC
Yield: 62.6 %

Procedure:
1-(i) To a mixture of 2-cyanobenzaldehyde (5.0 g), methyl 4,4-dimethoxyacetoacetate (7.39 g) and acetic acid (0.458 g) in benzene (15 ml) was added portionwise each one third of a solution of piperidine (390 mg) in benzene (5 ml) for each 20 minutes' interval. The mixture was heated to reflux for 2 hours and the resulting water was removed off azeotropically during the reaction course. After cooling, the reaction mixture was shaken with a mixture of benzene (50 ml) and water (30 ml), and the organic layer was separated and washed with diluted aqueous sodium bicarbonate solution and water. The aqueous washings were extracted with benzene (30 ml). The benzene extract was combined with the above organic layer, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The oily residue (14.8 g) was chromatographed on a column of silica-gel (200 g) and eluted with a mixture of benzene and ethyl acetate (25:1 v/v) to give an oily methyl 2 -(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (6.90 g). The thin layer chromatogram and N.M.R. spectrum of this product show that it consisted of a mixture of two stereoisomers.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CS(C)=O.O>[N:1]([CH2:6][C:7]#[C:8][CH2:9][N:10]1[CH2:33][CH2:32][CH2:31][C@:12]2([O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][C:18]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:13]2)[C@@H:11]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCCl)[C@H]2c2ccccc2)C1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(C(F)(F)F)cc1[C@H]1CO[C@]2(CCCN(CC#CCN=[N+]=[N-])[C@H]2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
Sodium azide (15 mg) was added to a solution of (3S,5R,6S)-7-(4-chlorobut-2-yn-1-yl)-3-[2-isopropoxy-5-(trifluoromethyl)phenyl]-6-phenyl-1-oxa-7-aza-spiro[4,5]decane (Description 75, 100 mg) in dimethylsulfoxide (1 ml). The mixture was stirred at room temperature overnight, diluted with water (20 ml) and extracted with ether (3×5 ml). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under pressure to give the title compound as a colorless oil (98 mg). m/z (ES+) m/z 513 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][CH:12]=[CH:11]3)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>CO>[N:14]1[C:15]2[C:10](=[CH:9][C:8]([C:5]3([C:3]([NH:19][NH2:20])=[O:2])[CH2:7][CH2:6]3)=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: NN
Reactant: COC(=O)C1(c2ccc3ncccc3c2)CC1
Solvent: CO
Solvent: O
Product: NNC(=O)C1(c2ccc3ncccc3c2)CC1
Yield: 99.9 %

Procedure:
A solution of 1-quinolin-6-yl-cyclopropanecarboxylic acid methyl ester (513 mg, 2.26 mmol) and hydrazine monohydrate (3.39 g, 67.7 mmol) in methanol (5 mL) was heated under reflux overnight. After cooling, the solvent was removed in vacuo to afford 513 mg (100%) of the title compound and used without further purification. LCMS (method A): [MH]+=228, tR=2.88 min.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)#[CH:12].N>>[N:5]1[CH:6]=[CH:7][N:8]=[CH:9][C:4]=1[C:3]1[CH:12]=[C:11]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[O:1][N:2]=1
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1ccc(C#N)cc1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cnccn3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 4-ethynylbenzonitrile (Aldrich, 64 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.62 (s, 1H), 7.92 (dt, J=8.5, 1.7 Hz, 2H), 8.13 (dt, J=8.5, 1.7 Hz, 2H), 8.71 (d, J=2.4 Hz, 1H), 8.77 (dd, J=2.6, 1.4 Hz, 1 H), 9.31 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [F-:1].[K+].[Br:3][C:4]([F:12])([F:11])[C:5]([F:10])([F:9])[C:6]([F:8])=[O:7].S(F)(O[C:17]([F:24])([F:23])[C:18]([F:22])=[C:19]([F:21])[F:20])(=O)=O.O>COCCOCCOC>[F:20][C:19]([F:21])=[C:18]([F:22])[C:17]([F:24])([F:23])[O:7][C:6]([F:1])([F:8])[C:5]([F:10])([F:9])[C:4]([F:12])([F:11])[Br:3]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: [F-]
Reactant: O=C(F)C(F)(F)C(F)(F)Br
Agent: [K+]
Solvent: COCCOCCOC
Solvent: O
Product: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)Br
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A suspension of 35.9 g (0.617 mol) of flame-dried KF in 750 ml of diglyme was stirred at 0° while 140.0 g (0.617 mol) of 3-bromotetrafluoropropionyl fluoride from part B was added. The mixture was stirred at 0°-5° for another 30 min and then was treated with 141.9 g (0.617 mol) of perfluoroallyl fluorosulfate. The reaction mixture was stirred for 4 h at 0°-5° and then poured into 3 liters of water. The resulting lower layer was washed with 500 ml of water, dried over CaSO4, and distilled to give 132.5 g (57%) of perfluoro(7-bromo4-oxa-1-heptene), bp 96°-99°, trace impurity only by GC. A sample from a similar synthesis was analyzed. IR (CCl4): 5.59μ (CF=CF2). NMR (CCl4): 19F -64.4 (t of m, JFF 9.9 Hz, 2 F, CFBr), -71.9 (d of d of t of d, JFF 24.9, 13.8, ~ 13, 7.3 Hz, 2F, OCF2C=), -82.8 (t of t of m, JFF ~13, 9.9 Hz, 2F, CF2O), -92.0 (d of d of t of t, JFf 52.0, 39.3, 7.3 Hz, 1F, cis-CF2 =CFF), -105.3 (d of d of t, JFF 117.7, 52.0, 24.9 Hz, 1F, trans-CF2CF=CFF), -121.9 (m, 2F, CF2), and -190.6 ppm (d of d of t of t, JFF 117.7, 39.3, 13.8, 1.6 Hz, 1F, CF2CF=).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][CH2:39][CH:40]1[O:44][C:43](=[O:45])[CH:42]=[C:41]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.Cl>O1CCCC1>[OH:36][CH2:37][CH2:38][CH2:39][CH:40]1[O:44][C:43](=[O:45])[CH:42]=[C:41]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC(C)(C)[Si](OCCCC1OC(=O)C=C1c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1C=C(c2ccccc2)C(CCCO)O1
Reaction time: 3 h
Yield: 71.7 %

Procedure:
1M Solution of tetrabutylammonium fluoride in tetrahydrofuran (0.736 ml) was added to a solution of 5-[3-(t-butyldiphenylsilyloxy)propyl]-4-phenyl-2(5H)-furanone (280 mg) in tetrahydrofuran (3 ml) and the resulting mixture was stirred at same temperature for 3 hours. The reaction mixture was poured into a mixture of ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine successively, dried over magnesium sulfate, and evaporated in vacuo to give 5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone (96 mg).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[F:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:10]=1[CH2:11][N:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[S:2](=[O:4])(=[O:3])[NH:5][C:6]1=[O:7]
Reactant: Fc1cccc(F)c1CNc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: O=C1NS(=O)(=O)c2ccccc2N1Cc1c(F)cccc1F
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 366 %

Procedure:
A solution of chlorosulfonylisocyanate (0.29 mL, 3.33 mmol) in nitroethane (5 mL) was cooled to approximately −40° C. and a solution of N-(2,6-difluorobenzyl)aniline (562 mg, 2.56 mmol) in nitroethane (3 mL) was added dropwise over approximately 10 min. The mixture was stirred at −40° C. for approximately 10 min, then at 0° for 15 min. Aluminium chloride (479 mg, 3.59 mmol) was then added and the mixture heated at reflux for 30 min before cooling to rt. Separately, the process was repeated using chlorosulfonylisocyanate (1.20 mL, 13.8 mmol) in nitroethane (20 mL), N-(2,6-difluorobenzyl)aniline (2.32 g, 10.6 mmol) in nitroethane (15 mL), followed by aluminium chloride (1.97 g, 14.8 mmol). The two reaction mixtures were combined and cautiously added to stirred ice-H2O (approximately 100 mL) and the title compound (3.04 g, 9.37 mmol) was isolated by filtration.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][N:2]([C@H:3]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:33]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)[C@H](Cc1ccccc1)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a solution of (2R)-2-(N-Methylamino)-3-phenyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-propan-1-one (free-base, 14 mg, 0.037 mmol) in 1,2-dichloroethane was added a solution of formaldehyde (37% w/w, 50 μL, 0.61 mmol) and then Na(OAc)3BH (0.12 mmol). The reaction mixture was stirred at room temperature for 3 hours, after which saturated NaHCO3 was added, and the reaction mixture was stirred 10 minutes. The suspension was extracted with DCM, and the combined extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation. The residue was filtered through a Fluorosil plug with ETOAC, and the filtrate was concentrated by rotary evaporation. The resulting residue was dissolved in ether and excess 4M HCl/dioxane was added. The yellow solids were isolated by filtration with nitrogen pressure and dried under reduced pressure to afford the desired product (7 mg, 41%) as the dihydrochloride salt. Rt 2.20. MS (ESI+) [M+H]+ 390.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1)[N:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12]
Reactant: C1=COCCC1
Reactant: COC(=O)c1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Yield: 82 %

Procedure:
A suspension of methyl 5-bromo-1H-indazole-3-carboxylate (CXVI) (1.35 g, 5.29 mmol), pyridinium p-toluenesulfonate (0.143 g, 0.56 mmol) and 3,4 dihydro-2H-pyran (1.02 mL, 11.90 mmol) in anhydrous dichloroethane (20 mL) was refluxed 5 h under argon. The suspension was turned into the clear solution. The solution was cooled and the excess solvent was evaporated under vacuum. The residue was dissolved in EtOAc and washed with dilute NaHCO3 solution (satd. NaHCO3 soln/H2O: 1:9). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (100% hexanes→5:95 EtOAc:hexanes) to get methyl 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylate (CXVII) as a white solid (1.47 g, 4.34 mmol, 82% yield). 1H NMR (DMSO-d6) δ ppm 8.22 (d, J=1.4 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.68 (dd, J=7.2, 1.6 Hz, 1H), 6.02 (dd, J=8.0, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (m, 1H), 3.79 (m, 1H), 2.37-2.31 (m, 1H), 2.05-1.96 (m, 2H), 1.77-1.73 (m, 1H). 1.60-1.58 (m, 2H); ESIMS found for C14H15BrN2O3 m/z 340.0 (M+H).
Reaction SMILES: [CH:1]1([N:4]([CH2:34][CH2:35]O)[C:5]([C:7]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)=[O:6])[CH2:3][CH2:2]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C.O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:35][CH2:34][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccn4)CCCC3)n2CCN1C1CC1
Reaction time: 1 h
Yield: 349.9 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacidcyclopropyl-(2-hydroxyethyl)-amide (451) (80 mg, 0.164 mmol), in dichloromethane (6 mL), TPP (150.33 mg, 0.574 mmol) and diisopropyl azodicarboxylate (0.097 mL, 0.492 mmol) were added and stirring was continued for 1 h at room temperature while silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.2). After completion of the reaction, water (5 mL) was added and the mixture was extracted with dichloromethane (2×25 mL). The combined extracts were dried and concentrated to get crude 9-benzyloxy-2-cyclopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (452) (270 mg, Crude) as a yellow gummy liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[NH:31])OCC)=[CH:22][CH:21]=1>C(O)C>[ClH:17].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:27](=[NH:31])[CH2:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ncccc1OCc1ccc(F)cc1
Reactant: CCOC(=N)Cc1ccc(OC)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC(=N)Nc2ncccc2OCc2ccc(F)cc2)cc1
Yield: 14.9 %

Procedure:
A mixture of 2-amino-3-(4-fluorobenzyloxy)pyridine (4.36 g, 20 mmol) and ethyl 4-methoxyphenylacetimidate hydrochloride (5.04 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil, which was purified by flash chromatography (chloroform/methanol) to obtain the product as a hygroscopic gum (1.2 g), m.p. 199°-200° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:15]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[N:9]2[CH3:15])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)CC(=O)Nc2cc(Br)ccc21
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)CC(C)(C)c2ccc(Br)cc21
Reaction time: 18 h

Procedure:
7-bromo-4,4-dimethyl-3,4-dihydroquinolin-2(1H)-one (210 mg, 0.83 mmol) and K2CO3 (335 mg, 2.42 mmol) were taken up in DMF (5 mL). Iodomethane (0.15 mL, 2.4 mmol) was added and the resulting mixture was stirred for 18 h. Water was added, and the resulting solids were filtered and washed with additional water to provide crude 7-bromo-1,4,4-trimethyl-3,4-dihydroquinolin-2(1H)-one that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2cccnc2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4cccnc4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(pyridin-3-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-N-methyl-2-(4-(pyridin-3-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (50% EtOAc/hexanes) gave the product as an off white solid (0.126 g, 35% yield). MS: m/z 508.2 [M+H]+.