Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])=[O:10])=[N+]=[N-].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])=[O:10]
Reactant: [N-]=[N+]=NCCCCCC(=O)Nc1ccccc1[N+](=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCCCCC(=O)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.7 %

Procedure:
To a mixture of 3 (13.5 g, 48.7 mmol), THF (100 mL) and water (50 mL) was added triphenyl phosphine (14.05 g, 53.5 mmol). The resulting mixture was stirred at room temperature for 6 hours. The THF and water were removed in vacuo. The residue was dissolved in the minimal amount of dichloromethane and passed through a silica gel pad (50 g) and washed with dichloromethane (500 mL) followed by a 4:1 mixture of dichloromethane-5% ammonia in methanol (500 mL). The appropriate fractions were concentrated and recrystallized from ethyl acetate to yield 6.45 g of 4 as a pale yellow solid.
Reaction SMILES: [C:1]([NH:5][NH2:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10].O>C(O)C>[C:1]([NH:5][NH:6][C:9](=[O:10])[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:12][OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1OCc2ccccc21
Reactant: CC(C)(C)NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NNC(=O)c1ccccc1CO
Yield: 13.5 %

Procedure:
t-Butylhydrazine (0.1 mol) in 75 ml ethanol was treated with 50% aqueous sodium hydroxide (0.11 mol). Phthalide (0.1 mol) was added and the mixture was refluxed for 5 days. After cooling, water was added and the crude product was isolated by filtration. Filtration through silica gel afforded N'-t-butyl-N-(2-hydroxymethylbenzoyl)hydrazine (3.0 g). m.p. 116-118° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4].[H-].[Na+].Br[CH2:29][C:30]1[CH:34]=[C:33]([C:35]2[S:36][C:37]([Cl:40])=[CH:38][CH:39]=2)[O:32][N:31]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]3)[N:11]([CH2:29][C:30]3[CH:34]=[C:33]([C:35]4[S:36][C:37]([Cl:40])=[CH:38][CH:39]=4)[O:32][N:31]=3)[C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2[nH]c(C(=O)NC3CCN(C(C)C)CC3)cc2c1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cnc2c(c1)cc(C(=O)NC1CCN(C(C)C)CC1)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a solution of 1.2 g 2-(1-Isopropyl-piperidin-4-ylcarbamoyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester in 20 mL DMF, 91 mg sodium hydride (95%) were added at 0° C. Then the reaction mixture was warmed to RT and stirred for 30 min. After cooling again to 0° C., 967 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. Then 50 mL of water were added and the precipitate was collected by filtration to yield 630 mg pure product. The filtrate was concentrated under reduced pressure and the residue purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). After lyophilization further 371 mg of product were obtained as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:36]4[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:34][CH2:35]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COCCN1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: COCCN1CCN(Cc2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 74.8 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.264 mmol) and 1-(2-methoxyethyl)piperazine (42 mg, 0.291 mmol) gave 7-cyclopentyl-2-{5-[4-(2-methoxy-ethyl)-piperazin-1-ylmethyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 71%) [following SiO2 chromatography, eluting with 0-10% (2M NH3 in MeOH)/dichloromethane]. MS (ESI) m/z 507.3 (M+H)− (method A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[C:6]([C:8]2[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17](OCC)=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1.[CH2:41]([NH2:44])[CH2:42][CH3:43]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[F:40])=[C:6]([C:8]2[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:10]([CH3:23])=[C:11]3[C:16]=2[CH:15]=[C:14]([C:17]([NH:44][CH2:41][CH2:42][CH3:43])=[O:18])[NH:13][C:12]3=[O:22])[CH:7]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Reactant: CCCN
Solvent: CO
Product: CCCNC(=O)c1cc2c(-c3cc(N)ccc3Oc3ccc(F)cc3F)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Yield: 97.5 %

Procedure:
A mixture of Example 4e (0.05 g, 0.088 mmol) and propan-1-amine (1 mL, 12.16 mmol) in methanol (0.5 mL) in a sealed tube was heated by microwave at 120° C. for 2 hours, cooled and concentrated to afford the title compound (0.05 g, 98%). The product was used without purification.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/N(C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32]([NH:36][NH2:37])[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[F:25][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:36]([C:32]5[CH:33]=[CH:34][CH:35]=[C:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH:31]=5)[N:37]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Reactant: CS(=O)(=O)c1cccc(NN)c1
Product: CS(=O)(=O)c1cccc(-n2nccc2-c2nn(-c3ccc4c(c3)OC(F)(F)O4)ccc2=O)c1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and (3-methane sulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=473.2 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.[N+](=[CH:30][Si](C)(C)C)=[N-].CO>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:20][CH:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)[C:17]([O:19][CH3:30])=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH2:2][CH2:3]1
Reactant: O=C1CCC(C[C@@H](C(=O)O)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](CC1CCC(=O)CC1)c1ccc(S(=O)(=O)C2CC2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(4-oxocyclohexy)propanoic acid (45 mg), diazomethyltrimethylsilane (2.0 M diethyl ether solution, 0.1 mL), methanol (0.2 mL), and toluene (0.8 mL) was stirred at room temperature for 10 minutes. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=50:50) to obtain methyl (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-(4-oxocyclohexyl)propanoate (29 mg) as a colorless oil.
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:64]([O:66][C:67](=[O:71])[CH2:68][CH2:69][NH2:70])[CH3:65]>CN(C=O)C>[CH2:64]([O:66][C:67](=[O:71])[CH2:68][CH2:69][NH:70][C:23](=[O:24])[CH:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C@@H:11]1[CH2:26][CH2:27][CH2:28][N:10]1[S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:29])=[CH:2][CH:3]=1)(=[O:8])=[O:9])[CH3:65]
Reactant: CCOC(=O)CCN
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)C(Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To N-(toluene-4-sulfonyl)-L-prolyl-L-phenylalanine (˜2 eq.) in DMF was added BOP (˜2.1 eq.) and NMM (˜4 eq.), and the reaction was stirred at room temperature for about 45 minutes. β-alanine ethyl ester (˜2 eq.) was added and the reaction stirred for about 16 hours at room temperature. The reaction mixture was extracted with water and diethyl ether. The combined organic solution was then washed with 0.2 N HCl, sat. NaHCO3 and sat. NaCl solutions. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% EtOAc/Hexane, Rf=0.18) to yield the title compound as a colorless oil, which was determined to be a mixture of diastereomers, by NMR.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[N:12][CH:13]=1.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]([C:8]1[CH:13]=[N:12][C:11]([NH:14][C:15]([C:17]2([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (56 μl, 0.72 mmol) was added slowly to the mixture of 1-benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid {5-[hydroxy-(2-methoxy-phenyl)-methyl]-pyridin-2-yl}-amide (50 mg, 0.12 mmol) and DIEA (24 μl, 0.14 mmol) in dichloromethane (2 ml) at 0° C. The reaction mixture was stirred at ambient temperature for 3 h. Solvents were evaporated and the residue was used for the next step without any additional purification.
Reaction SMILES: C([Mg]Br)C.[CH:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:19]([CH:21]=[CH2:22])=[O:20].[Cl-].[NH4+]>C(OCC)C.O>[CH2:22]=[CH:21][CH:19]([OH:20])[C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CC=O
Reactant: C#CCCCCCCCCCCCC
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: C=CC(O)C#CCCCCCCCCCCCC
Temperature: -10 °C

Procedure:
To freshly prepared ethyl magnesium bromide (from 58.95 mmoles of bromoethane and 49.36 mmoles of magnesium) in diethyl ether (125 ml) was added 1-tetradecyne (44.5 mmoles) in diethyl ether (25 ml) dropwise at ambient temperature. After 3 hours the reaction mixture was cooled to -10° C. and freshly distilled acrolein (59.86 mmoles) in diethyl ether (25 ml) was added dropwise. After 30 minutes saturated ammonium chloride (100 ml) and water (50 ml) were added. The organic phase was separated, washed with brine (100 ml) and dried over anhydrous magnesium sulfate. The desired compound was purified by flash chromatography on silica gel eluted with 90:10 hexane:ethyl acetate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:6]1=[O:16].[CH3:17][C:18](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:19]>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:18](=[O:19])[CH3:17])[C:6]1=[O:16]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: COCCn1cc(-c2ccccc2)[nH]c1=O
Product: COCCn1cc(-c2ccccc2)n(C(C)=O)c1=O

Procedure:
Approximately 21.8 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 120 ml. of acetic anhyride is refluxed together for four hours. The acetic anhydride is distilled out at reduced pressure. The residual semisolid is recrystallized from ether to yield the title compound as a white solid; m.p. 73°-75° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Br[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)[CH2:17][CH2:18]1)=[N:7]2
Reactant: Brc1cccnc1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: Cc1c(N2CCN(c3cccnc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50.0 mg, 0.11 mmol) and 3-bromopyridine in toluene to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(pyridin-3-yl)piperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.53 (1H, d, J=2.9 Hz), 8.11 (1H, d, J=4.3 Hz), 7.89 (1H, d, J=2.2 Hz), 7.72-7.80 (2H, m), 7.63-7.71 (1H, m), 7.53 (1H, d, J=8.4 Hz), 7.41 (1H, dd, J=9.6, 1.4 Hz), 7.12 (1H, t, J=2.2 Hz), 6.86 (1H, ddd, J=13.3, 8.5, 2.4 Hz), 3.85-3.94 (4H, m), 3.70-3.80 (4H, m), 3.52-3.61 (4H, m), 3.24-3.36 (4H, m), 2.22 (3H, s). Mass Spectrum (ESI) m/e=518.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:37])[CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(C=Cc4ccccc43)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 36.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.03 g, 0.06 mmol) obtained in step 2 and ethanesulfonamide (0.032 g, 0.30 mmol), the title compound (0.013 g, 37%) was obtained.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.B([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]2)=[CH:29][CH:28]=1)(O)O>>[O:41]=[S:37]1(=[O:40])[CH2:38][CH2:39][N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:2]3[N:10]4[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]5[CH:17]=[CH:16][C:15]([N:18]6[CH2:19][CH2:20][O:21][CH2:22][CH2:23]6)=[CH:14][CH:13]=5)=[N:9]4)=[CH:4][CH:3]=3)=[CH:28][CH:29]=2)[CH2:35][CH2:36]1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: O=S1(=O)CCN(Cc2ccc(B(O)O)cc2)CC1
Product: O=S1(=O)CCN(Cc2ccc(-c3ccc4cnc(Nc5ccc(N6CCOCC6)cc5)nn34)cc2)CC1

Procedure:
{7-[4-(1,1-Dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl}-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 4-[(4-boronophenyl)methyl]-thiomorpholine 1,1-dioxide in an analogous manner to Example 1031b. Product isolated as a yellow solid (36 mg, 24%). m.p.=251-255° C.; LCMS (m/e) 519 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 8.13 (d, 2H, J=7.8 Hz), 7.55 (d, 2H, J=7.4 Hz), 7.42 (d, 2H, J=7.8 Hz), 7.02-6.97 (m, 1H), 6.92 (d, 2H, J=7.0 Hz), 6.85-6.80 (m, 1H), 6.73-6.64 (m, 1H), 3.93-3.85 (m, 4H), 3.73 (s, 2H), 3.17-3.00 (m, 12H).
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[CH3:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14]>>[CH3:10][O:9][C:7](=[O:8])[C:6]([CH2:12][C:13](=[O:14])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:11]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(=O)CC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 88.5 %

Procedure:
57.2 g (1.06 mols) of sodium methylate are suspended in 400 g of dehydrated pinacolin. 118 g of molten oxalic acid dimethyl ester are added dropwise to the suspension in the course of 1 hour. The temperature is kept at 10° C. during this addition. The mixture is subsequently stirred for 15 minutes and 84 g of a methanol/pinacolin mixture are then distilled off at 64° C. The bottom product is cooled to 50° C. and 252 g of aqueous sulphuric acid (20.9% strength by weight) are added. Separation of the phases and subsequent distillation of the organic phase gives 164.6 g of pivaloylpyruvic acid methyl ester (87.8% of the theoretical yield), purity: 99.3%.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>CN1CCCC1=O>[CH:26]1([CH2:25][N:3]2[C:2]([N:33]3[CH2:34][CH2:35][CH:31]([N:30]([CH3:36])[CH3:29])[CH2:32]3)=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:17]2[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[N:7][C:8]=3[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:28][CH2:27]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(N(C)C)C3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 46 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 3-(dimethylamino)pyrolidine (285 mg, 2.49 mmol) and the resulting mixture was stirred at 120° C. for 3.5 hours. The reaction mixture was partitioned with chloroform and saturated brine and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, then methylene chloride-ether was added to the residue, and the precipitate was collected by filtration, washed with ether, and dried under reduced pressure to give the title compound (55 mg, 46%) as a pale orange solid.
Reaction SMILES: IC.[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([C:14]2[CH:18]=[N:17][NH:16][N:15]=2)[N:6]=1.[C:19](=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([C:14]2[CH:18]=[N:17][N:16]([CH3:19])[N:15]=2)[N:6]=1
Reactant: COc1nc(-c2cn[nH]n2)ccc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1nc(-c2cnn(C)n2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 19.2 %

Procedure:
Iodomethane (330 μL, 5.31 mmol) was added to a solution of 2-methoxy-3-nitro-6-(2H-1,2,3-triazol-4-yl)pyridine (Preparation 199, 235 mg, 1.063 mmol) and potassium carbonate (294 mg, 2.125 mmol) in THF (5.1 mL). The reaction mixture was stirred at room temperature for 72 hours. The solid was filtered and the filtrate concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 80/20 to 40/60 to afford the title compound as a beige solid (48 mg, 19%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(N2C(=O)[C:47](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:46]([C:61]3C=CC(S(C)(=O)=O)=CC=3)[CH:45]=N2)C=CC=1.N>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:45][CH:46]([CH3:61])[CH3:47])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Agent: N
Solvent: O
Product: CC(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (prepared as an intermediate in Example 375) in place of 2-(3-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-4-tosyloxy-3(2H)-pyridazinone (yield: 0.486 g, 100%). mp 121–128° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=7 Hz, 6H), 1.84 (m, 1H), 3.30 (s, 3H), 4.20 (d, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.92 (m, 2H), 8.07 (m, 2H), 8.19 (s, 1H). MS (DCI/NH3) m/z 417 (M+H)+, 434 (M+NH4)+. Anal. calc. for C21H21FN2O4S.0.50 H2O: C, 59.28; H, 5.21; N, 6.58. Found: C, 59.49; H, 4.97; N, 6.34.