Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:16])[C:6]1=[O:17])([OH:3])=[O:2].[N+:18]([O-])([O-:20])=[O:19].[Na+]>S(=O)(=O)(O)O>[C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:16])[C:6]1=[O:17])([OH:3])=[O:2]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccc(Cl)cc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
13.0 g (51 mmol) of 1-(carboxymethyl)-7-chloro-2,3(1H,4H)-quinoxalinedione were dissolved in 150 ml of concentrated sulfuric acid and, at 0° C., 4.3 g (51 mmol) of sodium nitrate were added a little at a time. The mixture was stirred at room temperature for 2 h and then poured into ice-water, and the precipitate was filtered off with suction to yield 10.2 g (67%) of the product. Melting point >280° C.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16](Br)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:20]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)#[CH:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16]([C:21]#[C:20][C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 2.0 g of 2-pivaloylamino-4-hydroxy-6-bromopyrido[2,3-d]pyrimidine (prepared according to Example 6), 1.31 g of tert.-butyl 4-ethynylbenzoate, 2.57 ml of triethylamine, 0.11 g of palladium chloride, 0.32 g of triphenylphosphine, and 0.05 g of cuprous iodide in 150 ml of acetonitrile is heated at reflux under nitrogen for 2.5 hours. The reaction mixture is cooled to room temperature and then in an ice bath. The solid is collected and washed with small portions of cold acetonitrile to yield 1.91 g (69%) of 2-pivaloylamino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish powder, which is sufficiently pure for the next reaction. A small sample of this solid, purified further by chromatography on silica gel using a 5% methanol:methylene chloride mixture as the eluent, had the following constants: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.37 (s, 9H), 1.63 (s, 9H), 7.61 (d, 2H, J=8.50 Hz), 8.02 (d, 2H, J=8.50 Hz), 8.42 (brs, 1H), 8.66 (slightly brs, 9.01 (slightly brs, 1H);IR (KBr) 3200, 2980, 1710, 1670, 1600, 1545, 1440, 1375, 1290, 1140, and 770 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[CH:34]=[CH:33][NH:32][C:29]2=[N:30][CH:31]=1)(=[O:25])=[O:24]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:32]3[C:29]4=[N:30][CH:31]=[C:26]([S:23]([CH3:22])(=[O:24])=[O:25])[CH:27]=[C:28]4[CH:34]=[CH:33]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: CS(=O)(=O)c1cnc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)cnc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (intermediate-25).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:57][O:58][CH2:59][C:60]([CH3:64])([NH2:63])[CH2:61][NH2:62]>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:63][C:60]([CH3:64])([CH2:59][O:58][CH3:57])[CH2:61][NH:62][C:16]([C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])[C:7]2=[N:14][C:13]=1[CH3:15])=[O:17]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: COCC(C)(N)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCC(C)(N)CNC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
180 mg (0.57 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 3A, 237 mg (0.62 mmol) of HATU and 0.30 ml (1.70 mmol) of N,N-diisopropylethylamine were initially charged in 3.6 ml of DMF, and the mixture was stirred at RT for 20 min. 74 mg (0.62 mmol) of rac-3-methoxy-2-methylpropane-1,2-diamine were then added and the reaction mixture was stirred at RT overnight. The reaction solution was diluted with water/TFA and purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was concentrated. The residue was taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 136 mg (56% of theory, purity 98%) of the title compound.
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])=O.B(F)(F)F.CCOCC>C(Cl)Cl>[SH:1][CH2:2][CH:3]1[CH2:4][S:5][C:10]([CH3:12])([CH2:9][CH2:8][C:7]([O:14][CH2:15][CH3:16])=[O:13])[S:6]1
Reactant: SCC(S)CS
Reactant: CCOC(=O)CCC(C)=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCC1(C)SCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 1,2,3-trimercaptopropane (5.6 g, 0.04 mol), ethyl levulinate (5.8 g, 0.04 mol) and boron trifluoride etherate (1.25 ml) in methylene chloride (150 ml). The crude product was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 3.35 g (31%) of product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH:17]=2)[C:9]([F:19])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]>O.[Pd]>[F:2][C:3]1[CH:11]=[C:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[C:9]([F:19])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CN1CC=C(c2cc(F)c(C(=O)O)cc2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Product: CN1CCC(c2cc(F)c(C(=O)O)cc2F)CC1

Procedure:
2.53 g (10 mmoles) of 2,5-difluoro-4-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)benzoic acid hydrochloride in 100 ml water with 10% Pd/C catalyst was hydrogenated under pressure. Filtration and evaporation afforded the title compound.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12](Cl)=[O:13])[N:9]=[CH:8]2)[CH:2]=1.C(N(CC)CC)C.Cl.[CH3:29][NH:30][O:31][CH3:32]>ClCCl>[CH3:32][O:31][N:30]([CH3:29])[C:12]([C:10]1[N:9]=[CH:8][N:7]([C:3]2[CH:2]=[C:1]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][CH:4]=2)[CH:11]=1)=[O:13]
Reactant: CNOC
Reactant: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
The above product (11a) was dissolved in dichloromethane (20 ml). Triethylamine (10 ml) and N,O-dimethylhydroxylamine hydrochloride (0.83 g, 8.3 mmol) were added and the resultant mixture was stirred at ambient conditions overnight. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography on silica gel using a mixture of 0.8% methanol in chloroform as the eluent to afford 12a (1.2 g).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[C:31]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:24]5([C:43]6[C:42](OC)=[CH:41][CH:40]=[C:39]([C:46]7[N:51]=[C:50]([C:52]8[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=8)[N:49]=[C:48]([C:58]8[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=8)[N:47]=7)[C:38]=6[C:37]6[C:32]5=[CH:33][CH:34]=[CH:35][CH:36]=6)[C:23]=4[C:22](OC)=[CH:21][CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N2C(Cl)=NN=N2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:58]1([C:48]2[N:49]=[C:50]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[N:51]=[C:46]([C:39]3[C:38]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[C:24]5([C:23]6[CH:22]=[CH:21][CH:20]=[C:19]([C:9]7[N:8]=[C:7]([C:1]8[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=8)[N:12]=[C:11]([C:13]8[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=8)[N:10]=7)[C:31]=6[C:30]6[C:25]5=[CH:26][CH:27]=[CH:28][CH:29]=6)[C:43]=4[CH:42]=[CH:41][CH:40]=3)[N:47]=2)[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: COc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c2c1C1(c3ccccc3-2)c2ccccc2-c2c(-c3nc(-c4ccccc4)nc(-c4ccccc4)n3)ccc(OC)c21
Agent: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cccc4c3-c3ccccc3C43c4ccccc4-c4c(-c5nc(-c6ccccc6)nc(-c6ccccc6)n5)cccc43)n2)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A well-stirred suspension of 41.9 g (50 mmol) of 4,4′-bis(4,6-diphenyl-1,3,5-triazin-2-yl)-1,1′-dimethoxy-9,9′-spirobifluorene, 18.1 g (100 mmol) of 1-phenyl-5-chlorotetrazole and 27.6 g (200 mmol) of K2CO3 is heated under reflux for 18 h in 250 ml of acetone. After cooling, the precipitated solid is filtered off with suction and dried. The solid is dissolved in 200 ml of toluene, 6 g of Pd/C (5%) are added, and the mixture is stirred at 40° C. for 8 h under a hydrogen atmosphere. After removal of the solvent, the residue is washed three times with 50 ml of ethanol:water (1:1, v:v) and three times with 100 ml of ethanol and subsequently recrystallised three times from DMF (about 10 ml/g). Yield: 25.6 g (32.96 mmol), 66.0%, purity: 99.9% (HPLC).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[S:15][C:10]2[NH:11][C:12](=[O:14])[CH2:13][C:9]=2[CH:8]=1)[CH3:2].[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>N1CCCCC1.CC(O)C>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]\[C:7]1[S:15][C:10]2[NH:11][C:12](=[O:14])[C:13](=[CH:22][C:18]3[NH:17][CH:21]=[CH:20][CH:19]=3)[C:9]=2[CH:8]=1)[CH3:2]
Reactant: O=Cc1ccc[nH]1
Reactant: CCOC(=O)C=Cc1cc2c(s1)NC(=O)C2
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)/C=C\c1cc2c(s1)NC(=O)C2=Cc1ccc[nH]1
Temperature: 75 °C
Yield: 24.5 %

Procedure:
3-(5-Oxo-5,6-dihydro-4H-thieno[2,3-b]pyrrol-2-yl)-acrylic acid ethyl ester (30 mg, 0.13 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (0.15 mmol, 14 mg) was added in one portion and the mixture heated at 75° C. for 30 minutes. The reaction mixture was poured into an ice/water mixture (4 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of (Z)-3-[5-Oxo-4-(1H-pyrrol-2-ylmethylene)-5,6-dihydro-4H-thieno[2,3-b]pyrrol-2-yl]-acrylic acid ethyl ester as a red solid. MS(ES): mle 315 [M+H].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:21][C:22](C)([O-:24])[CH3:23].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]2[CH2:23][O:24]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCCCc2ccccc2O)cc1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 1(a), 3.04 g of 2-[4-(4-isopropylphenyl)butyl]phenol (prepared as described in Preparation 8), 1.27 g of potassium t-butoxide and 3.11 g of epibromohydrin were reacted in 60 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 3.23 g (yield 88%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:17]1(B(O)O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:10][C:7]1[CH:8]=[CH:9][C:2]([C:25]2[C:26]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][CH:24]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=Cc1cc(O)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(O)ccc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a suspension of 2-bromo-5-hydroxybenzaldehyde (300 mg, 1.49 mmol), sodium carbonate (190 mg, 1.79 mmol), and 1-naphthaleneboronic acid (384 mg, 2.23 mmol) in 3.0 mL of N,N-dimethylformamide/water (2:1) was added palladium acetate (18 mg, 80 μmol) under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered. The filtrate was diluted with ethyl acetate, and the solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) to obtain the title compound as a white solid (274 mg, 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:11](I)[CH3:12].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:11]([N:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:12]
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ncc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a solution of 4-nitro-2H-1,2,3-triazole (2.02 g, 17.7 mmol) in N,N-dimethylformamide (40 ml), sodium hydride (1.06 g, 26.6 mmol) was added at 0° C., and the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added ethyl iodide (4.15 g, 26.6 mmol), followed by stirring the mixture overnight at room temperature. To the reaction solution was added a saturated aqueous sodium bicarbonate solution, the mixture was then extracted with ethyl acetate, and the combined organic layers were washed with water and a saturated saline solution, then dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Biotage, hexane:ethyl acetate=5:1 to 1:4) to give 2-ethyl-4-nitro-2H-1,2,3-triazole (1.35 g, yield: 53%) as a pale yellow oily substance. 2) To a solution of nitro intermediate (1.35 g, 9.46 mmol), obtained in the above reaction, in methanol (30 ml), was added palladium carbon (500 mg, 50% wet, 4.70 mmol), followed by overnight stirring the mixture under hydrogen atmosphere at room temperature under a pressure of one atmosphere. The reaction solution was filtered through Celite to remove palladium carbon, and the solvent was concentrated under reduced pressure to give 2-ethyl-2H-1,2,3-triazol-4-amine (979 mg, yield: 92%) as a red oily substance. 3) Using 2-ethyl-2H-1,2,3-triazol-4-amine (979 mg, 8.73 mmol) obtained in the above reaction and 4-chloroquinazolin-6-ylacetate (1.94 g, 8.73 mmol), 4-[(2-ethyl-2H-1,2,3-triazol-4-yl)amino]quinazolin-6-ol (1.52 g, yield: 68%) was obtained as a gray solid by the method as in Example 76.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].[C:25](=[NH:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:26]1([C:25](=[N:38][C:2]2[CH:7]=[CH:6][C:5]3[C:8]4([CH2:23][O:24][C:4]=3[CH:3]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]4=[O:22])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCN1C(=O)C2(COc3cc(N=C(c4ccccc4)c4ccccc4)ccc32)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)one (0.10 g, 0.26 mmol) in anhydrous toluene (5.00 mL) was added benzophenone imine (0.09 g, 0.52 mmol), sodium t-butoxide (0.03 g, 0.36 mmol), tris(dibenzylideneacetone) dipalladium(0) (0.01 g, 0.07 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.12 g, 0.19 mmol). The reaction mixture was refluxed for 16 h, cooled down to ambient temperature, diluted with dichloromethane (50.0 mL) and filtered through a celite bed. The filtrate was concentrated in vacuo to dryness to give the title compound which was used in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([O:34]COC)[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][C:12]=3[CH3:24])[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([OH:34])[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:21])[CH3:22])=[CH:13][C:12]=3[CH3:24])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5C)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: Cc1cc(NC(=O)CN(C)C)ccc1-c1cc2c(-c3cnc(C4(O)CCC4)s3)c(Cl)cnc2[nH]1

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methylphenyl)-2-(dimethylamino)acetamide (Example 48C) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.28 (s, 1H) 9.80 (s, 1H), 8.34 (s, 1H) 8.23 (s, 1H) 7.64 (m, 2H) 7.52 (d, 1H) 6.67 (s, 1H) 6.61 (s, 1H) 3.09 (s, 2H) 2.62 (m, 2H) 2.44 (s, 3H) 2.40 (m, 2H) 2.29 (s, 6H) 1.96 (m, 2H); MS ESI(+) m/z 496.1 [M+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:29])[F:28])[C:8]([C:16]([O:18]CC)=O)=[C:9]([CH3:15])[NH:10]2)([CH3:3])[CH3:2].[H-].[Na+].[N:33]1C=NC=N[CH:34]=1>CN(C)C=O>[CH:1]([O:4][C:5]1[C:6]2[CH:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])[C:8]3[C:16](=[O:18])[NH:33][CH:34]=[CH:15][C:9]=3[NH:10][C:11]=2[CH:12]=[CH:13][N:14]=1)([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F
Reactant: c1ncncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nccc2c1C(c1ccccc1C(F)(F)F)c1c(cc[nH]c1=O)N2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 11.3 g (27 mMole) ethyl (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoro methylphenyl)-1,6-naphthyridine-3-carboxylate in 200 ml dimethylformamide is added dropwise, under an atmosphere of nitrogen, to a suspension of 1.0 g (33 mMole) sodium hydride (80% in oil) in 20 ml dry dimethylformamide. After cessation of the gas evolution, the reaction mixture is stirred for 10 minutes at ambient temperature and subsequently 2.5 g (31 mMole) s-triazine in 20 ml dimethylformamide are added dropwise thereto. The reaction mixture is stirred for 16 hours at 105° C. and, after cooling, evaporated in a vacuum. The residue is chromatographed on silica gel with dichloromethane/methanol (95:5 v/v) and the fraction with an Rf of 0.6 is isolated and recrystallized from ethyl acetate/ethanol (9:1 v/v). There is obtained (±)-1,2,5,10-tetrahydro-9-isopropoxy-1-oxo-10-(2-trifluoromethylphenyl)-pyrido[4,3-b][1,6]naphthyridine in the form of colorless crystals; mp 315° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[C:12]1[CH:22]=[C:16]2[N:17]([CH3:21])[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=1>>[CH3:21][N:17]1[CH2:18][CH2:19][CH2:20][N:15]2[C:14](=[O:23])[N:13]=[C:12]([O:1][CH2:2][C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=3)[C:6]#[N:7])[CH:22]=[C:16]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cccc(CO)c1
Product: CN1CCCn2c1cc(OCc1cccc(C#N)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 3-(hydroxymethyl)benzonitrile and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].C(O[CH:16]=[C:17]([C:23]#[N:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[NH2:24][C:23]1[N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[N:7]=[CH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: CC(C)(C)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C(C)(C)C)c1N
Yield: 100 %

Procedure:
A solution of tert-butylhydrazine monohydrochloride (13.9 g, 111.55 mmol), sodium acetate (11.44 g, 139.43 mmol) and ethyl 2-(ethoxymethylene)-2-cyanoacetate (19 g, 112.31 mmol) in ethanol (130 mL) was heated under reflux for 20 hr. Ethanol was evaporated under reduced pressure, and ethyl acetate was added to the residue. The solution was washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2→35% ethyl acetate/hexane) to give ethyl 5-amino-1-tert-butyl-1H-pyrazole-4-carboxylate (24 g, 111.55 mmol, 102%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5]>O1CCCC1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(CO)c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.6 %

Procedure:
A solution of 2-chloro-3-nitrobenzoic acid (1.0 g, 5.0 mmol) in tetrahydrofuran (10 mL) is cooled to 0° C. under an argon atmosphere. Boranetetrahydrofuran complex (6.4 mL of a 1.0 M solution) is added dropwise, maintaining a reaction temperature of less than 5° C. After the addition is complete, the reaction mixture is stirred for 6 hours at room temperature. It is then cooled in an ice bath and quenched by the addition of 10 mL of 1.0 N HCl. The reaction mixture is heated at reflux for 30 minutes and concentrated by distilling the THF. The remaining aqueous solution is extracted with methylene chloride, and the organic layer is washed with saturated aqueous bicarbonate and brine. Evaporation of the organic layer followed by recrystallization of the residue from hexane gives 2-chloro-3-nitrobenzenemethanol (0.4 g, 43%), mp=69-70° C.