Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:23].C(N(CC)CC)C>C(O)(C)C>[CH3:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][CH:40]=1)[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:33][CH2:34][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=2)[N:6]3[CH3:11])[CH2:36][CH2:37]1)=[O:23]
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Reactant: Cc1cccc(C(=O)NCc2ccccc2N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cccc(C(=O)NCc2ccccc2N2CCN(c3ncnc4c3nc(-c3cnn(C)c3)n4C)CC2)c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 3-methyl-N-(2-(piperazin-1-yl)benzyl)benzamide (46.4 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 31.5 mg (50% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([N+:34]([O-:36])=[O:35])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 48.9 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.11 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and the reaction mixture was heated to 80° C. overnight. The crude material was purified by silica gel chromatography (eluting with 0-35% ethyl acetate in hexanes) to yield the product (71 mg, 50%). ESI-MS m/z calc. 484.12. found 485.0 (M+1)+. Retention time 2.17 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)[CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C([BH3-])#N.[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH2:22][CH2:21][O:20][CH3:19])[CH:12]=2)[CH:3]=1
Reactant: COCCN
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCCNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 61.6 %

Procedure:
4-Chloro-2-(3-formylphenoxy)benzonitrile (0.20 g, 0.78 mmol), 2-methoxyethylamine (72 μL, 62 mg, 0.83 mmol) and sodium cyanoborohydride (60 mg, 0.96 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (20 mL) for 40 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.10 g, 0.86 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-{3-[(2-methoxyethylamino)methyl]phenoxy}benzonitrile fumarate (208 mg, 61%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27](O)[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51][Si](C(C)(C)C)(C)C)[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([O:63][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:71])[CH3:2].C(N(S(F)(F)[F:78])CC)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:78])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:61])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:59][CH3:60])[CH2:46]2)[CH:7]([CH3:62])[CH:6]([OH:63])[CH2:5][C:4]1=[O:71])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a stirred solution of 17-Ethyl-1,20-di-hydroxy-12-[2'-(4"-t-butyldimethylsilyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-t-butyldimethylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in methylene chloride cooled to -78° C. was added diethylaminosulfur trifluoride. After 3 min., saturated sodium bicarbonate solution was added followed by ethyl acetate and the reaction mixture was allowed to warm to room temperature. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 1:2+1% methanol. To a solution of this material (10 mg) in THF (0.6 ml) in a polypropylene vial was added 40 μL of HF-pyridine solution in THF. After stirring for 28 hours at rt, the mixture was added to a saturated solution of sodium bicarbonate. This mixture was extracted with ethyl acetate and the organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The product was purified by chromatography (silica, ethyl acetate:hexanes 2:1+1% methanol) to give the title compound. Mass Spectrum (FAB): 832 (M+Na)
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[CH:18][N+:19]([O-])=O)[CH2:9][C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](O)[CH3:24]>[Ni].O1CCCC1>[CH3:23][C:24]1[N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8](=[O:22])[CH2:9][C:10]2=[CH:18][N:19]=1
Reactant: CCO
Reactant: O=C1CC(=C[N+](=O)[O-])Nc2ccccc2N1c1ccccc1
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ncc2n1-c1ccccc1N(c1ccccc1)C(=O)C2
Reaction time: 20 h

Procedure:
Raney nickel, 11 g, was added to a solution of 3.5 g (0.0118 m) of 5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-one in 50 ml of tetrahydrofuran, and 150 ml of ethanol. The mixture was then hydrogenated at atmospheric pressure for a period of 20 hours. The catalyst was filtered off and washed with tetrahydrofuran and methylene chloride. The filtrate was evaporated and the remaining oil (3.1 g) was dissolved in 250 ml of xylene and 6.2 ml of triethylorthoacetate. After heating to reflux with stirring for 30 min, the reaction mixture was evaporated. The residue was dissolved in 200 ml of toluene and 19 g of activated manganese dioxide was added to the solution. The mixture was stirred and refluxed for 30 min. The manganese dioxide was filtered off and washed well with tetrahydrofuran and methylene chloride. The filtrate was evaporated, and the residue was crystallized from ethyl acetate to yield crystals with mp 217°-220°. For analysis, the material was recrystallized from methylene chloride/ethyl acetate to give colorless crystals with mp 221°-223°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(O)CCC>[N:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1ccncc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1cc(N2CCC3(CC2)OCCO3)ccn1
Yield: 58 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (10.0 g, 69.9 mmol, 1 eq) and 4-bromopyridine HBr (16.2 g, 83.7 mmol, 1.2 eq) were dissolved in n-butanol (120 ml) and DIPEA (23 ml, 139.8 mmol, 2.0 eq) and refluxed for 14 h. After monitoring by thin-layer chromatography, the reaction solution was concentrated under reduced pressure. After purification by column chromatography (silica gel, 3% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 58% (9.0 g, 40.9 mmol).
Reaction SMILES: CN1CC[N:5]([C:8]2[C:14]3=[CH:15][CH:16]=[CH:17][N:13]3[CH2:12][C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[N:9]=2)CC1.C(O)(=O)C>[Zn].C(O)C>[NH2:5][C:8]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[CH2:12][C:11]2[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=2[N:9]=1
Reactant: CN1CCN(C2=Nc3ccccc3Cn3cccc32)CC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: NC1=Nc2ccccc2Cn2cccc21
Temperature: 0 °C

Procedure:
A mixture of 20 g. of 1-(o-nitrobenzyl)-2-pyrrolecarbonitrile [M. Artico et al.; See Example 1], 50 g. of zinc dust, 40 ml. of glacial acetic acid and 200 ml. of ethanol is stirred at room temperature for about 24 hr. The reaction mixture is filtered to remove unreacted zinc dust and the precipitate is washed with alcohol. The filtrate is chilled to 0° C. and the precipitated zinc salts are removed by filtration; this filtrate is then evaporated to a solid residue which is dissolved in methylene chloride and filtered again. The solvent is removed by evaporation and the residue crystallized by the addition of ether; the product is collected and 11-amino-5H-pyrrolo[2,1-c]-[1,4]benzodiazepine, m.p. 179°-181° C., is thereby obtained.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N:12]=1)([OH:6])=[O:5].C(OC(=O)C)C>CCOCC>[C:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N:12]=1)([O:6][CH3:3])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCCNc1nc2ccccc2c(=O)o1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)CCCNc1nc2ccccc2c(=O)o1
Reaction time: 3 h

Procedure:
A solution of diazomethane in ether is added dropwise to a solution of 2-(3-carboxy-propylamino)-4H-3,1-benzoxazin-4-one in ether. The reaction is monitored by thin layer chromatography (silica gel, 10% ethylacetate in petroleum ether) until completion. A small amount of silica gel is added to the solution. The solution is allowed to stand for 3 hours, then filtered. The filtrate is evaporated to give 2-(3-carbomethoxypropylamino)-4H-3,1-benzoxazin-4-one.
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH:21]([CH3:23])[CH3:22])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:27])(=O)=O>ClCCl>[Cl:27][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH:21]([CH3:23])[CH3:22])[S:10]1(=[O:12])=[O:11]
Reactant: CC(C)c1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cccc2c1C(=O)N(CCl)S2(=O)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-Phenylthiomethyl-4-isopropylsaccharin (53.5 g), sulfuryl chloride (40 mL, 67.2 g) and dichloromethane (250 mL) were mixed with stirring at room temperature. The mixture underwent a slightly exothermic reaction and was allowed to stand for 17 hours at room temperature, then stripped of volatiles. The residue crystallized with hexane in three crops 33.65 g, m.r. 101°-102° C.; 3.45 g, m.r. 100°-101° C.; 0.45 g, m.r. 99°-100° C.; total, 38.55 g, 91% yield). The three crops were combined and recrystallized from isopropyl alcohol (30 mL)-cyclohexane (270 mL) affording 2-chloromethyl-4-isopropylsaccharin in two crops (33.5 g, m.r. 101°-102.5° C.; 2.65 g, m.r. 100°-101° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:18][OH:19])[CH:5]=[C:6]([O:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1.C(OCC)C>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH:18]=[O:19]
Reactant: Cc1cc(CO)cc(OCCNc2ccncc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(C=O)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of {3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-phenyl}-methanol (0.132 g) and manganese dioxide (0.370 g) in 1,4-dioxan (5 ml) was heated to reflux with stirring under an atmosphere of dry nitrogen for 5 h. After cooling to room temperature the mixture was filtered through Harborlite® and the pad washed with 1,4-dioxan and then methanol. The combined filtrates were evaporated to dryness under reduced pressure to give an off-white solid. Trituration with diethyl ether gave, after drying, the title compound as a white powder (0.074 g).
Reaction SMILES: [Si:1]([O:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]1[CH:15]=[C:14](I)[N:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Mg]Br)C.[CH3:23][Sn:24](Cl)([CH3:26])[CH3:25]>C(Cl)Cl>[Si:1]([O:8][C:9]([CH3:18])([CH3:17])[CH2:10][N:11]1[CH:15]=[C:14]([Sn:24]([CH3:26])([CH3:25])[CH3:23])[N:13]=[CH:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[Sn](C)(C)Cl
Reactant: CC(C)(Cn1cnc(I)c1)O[Si](C)(C)C(C)(C)C
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CC(C)(Cn1cnc([Sn](C)(C)C)c1)O[Si](C)(C)C(C)(C)C
Temperature: 10 °C
Yield: 74 %

Procedure:
To a mixture of 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-iodo-1H-imidazole in DCM was added ethylmagnesium bromide at −78° C. The temperature of the mixture was allowed to warm up to about 10° C. slowly and cooled again. Trimethyltin chloride was added dropwise at −78° C. After the addition, the temperature was allowed to slowly warm up to room temperature. The reaction mixture was pouted into saturate NH4Cl solution, then extracted with DCM. The organic phase was washed with water twice, dried over anhydrous Na2SO4, and concentrated to give 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(trimethylstannyl)-1H-imidazole (Yield=74%). LC-MS: m/z=419 [M+H+] 1H NMR (CDCl3, 400 MHz): δ 7.63 (s, 1H), 7.00 (s, 1H), 3.79 (s, 2H), 1.22-1.19 (s, 6H), 0.86 (s, 9H), 0.27 (s, 6H), 0.02 (s, 6H)
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a slurry of 0.33 g (8.3 mmol) of NaH (60% dispersion in oil) in 30 ml of dried dimethylformamide ("DMF"), was added 0.973 g (6.00 mmol) of commercially available (Lancaster, Windham, N.H.) 6-nitro-IH-indole (1) at 0-5° C. over a period of 10 minutes. After 1 hour stirring at the same temperature, 0.75 ml (12.1 mmol) of methyl iodide was added and the mixture was stirred at the same temperature for 30 minutes, then at room temperature for 1 hour, poured into ice and water and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated to yield 0.814 g (77.5%) of 1-methyl-6-nitro-1H-indole (2) as a yellow solid. This material was used without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:27]1([C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)O)[OH:28].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:23][C:22]([F:24])([F:25])[O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:28][C:27]3[CH:29]=[CH:31][CH:32]=[CH:33][C:34]=3[O:26]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(OC(F)(F)F)cc2)CC1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: FC(F)(F)Oc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 71.2 %

Procedure:
A solution of 4-(4-trifluoromethoxy-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 247) (373 mg, 1.0 mmol), catechol (440 mg, 4.0 mmol) and p-TsOH.H2O (380 mg, 2.0 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 44 hours. Standard work-up and purification gave 4-[2-(4-trifluoromethoxy-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (260 mg, 71%).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[N:3]=1.[C:13]([C:15]1([NH:24][C:25](=[O:35])[CH:26]([NH2:34])[CH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16]1)#[N:14].CN1CCOCC1>C(#N)C>[C:13]([C:15]1([NH:24][C:25](=[O:35])[CH:26]([NH:34][C:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][C:4](=[O:12])[N:3]=2)[CH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH3:23])[CH2:19][CH2:20]1)#[N:14]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CCC(C)(C)CC)CC1
Reactant: O=c1nc(Cl)c2ccccc2o1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCCN1CCC(C#N)(NC(=O)C(CCC(C)(C)CC)Nc2nc(=O)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A suspension of 4-chloro-benzo[e][1,3]oxazin-2-one (620 mg, 3.41 mmol, 2.0 eq), 2-amino-5,5-dimethyl-heptanoic acid (4-cyano-1-propyl-piperidin-4-yl)-amide (675 mg, 1.71 mmol, 1.00 eq), and 4-methylmorpholine (NMM) (0.56 mL, 5.09 mmol, 3.00 eq) in acetonitrile (9.0 mL) was stirred at room temperature overnight. The reaction mixture was then concentrated, resuspended in ethyl acetate (50 mL) and washed with saturated Na2CO3 solution. The organic phase was dried (MgSO4) and concentrated and the resulting residue was chromatographed over silica gel using a gradient of methanol in dichloromethane as the eluant to provide 124 mg (16% yield) of the title compound; m/z calculated for C26H37N5O3 467.6, found 468.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19]CCC[CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO>C(Cl)Cl>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([NH:20][CH:15]2[CH2:14][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[CH2:19]2)=[N:26][CH:25]=1
Reactant: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ccc23)C1
Solvent: ClCCl
Solvent: CO
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CC(Nc2ncnc3[nH]ccc23)C1
Yield: 51 %

Procedure:
A similar procedure was used as describe for the synthesis of 2-(3,5-dichlorophenylamino)-1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino) azepan-1-yl) ethanone to give a residue, that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (107 mg, 51%) the titled compound. 1H NMR (DMSO-d6, 400 MHz): 11.70 (s, 1H), 8.14 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.16 (s, 1H), 6.64 (s, 3H), 6.56 (s, 1H), 6.40 (bs, 1H), 4.94-4.80 (m, 1H), 4.58 (t, J=8.0 Hz, 1H), 4.30 (t, J=8.0 Hz, 1H), 4.16-4.04 (m, 1H), 3.98-3.86 (m, 1H), 3.78 (d, J=1.6 Hz, 2H). LC-MS: m/z [M+1]=391.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OC(=O)C)C>[C:1]([N:5]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCC(=O)NNC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1-t-butyl-2-valerylhydrazine (4 g, 0.023M) in toluene (40 ml) at 5° C. was added benzoyl chloride (3.4 g, 0.024M) and 50% aq. sodium hydroxide (0.98 g, 0.024M). After addition, the mixture was warmed to room temperature and stirred 2.5 hour. The mixture was diluted with ethylacetate (50 ml) and washed with water (2×25 ml) and brine (1×25 ml). The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford N'-t-butyl-N-valeryl-N'-benzoylhydrazine as a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:26])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Br)cc3F)c12
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-allyl-4-(4-bromo-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-ol (0.34 g, 0.84 mmol) (from Example 19, Step D, supra) in acetone (100 mL) was added K2CO3 (0.35 g, 2.52 mmol) and methyl iodide (1.19 g, 8.41 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4.5 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:4:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-bromo-2-fluoro-phenyl)-amine as a yellow solid. (Yield 0.33 g, 94%).