Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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>[CH2:1]([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:23]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCCC23CCNC3)cc1
Reactant: Brc1cncc(Oc2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCCC23CCN(c2cncc(Oc4ccccc4)c2)C3)cc1
Temperature: 90 °C
Yield: 75.7 %

Procedure:
1-Benzyl-1,7-diazaspiro[4.4]nonane (500.0 mg, 2.4 mmol) was dissolved in dry toluene (15 mL) in a 50 mL round bottom flask equipped with a magnetic stirring bar. Nitrogen was bubbled through the solution in a slow stream. To the stirring solution was added 3-bromo-5-phenoxypyridine (636.8 mg, 2.55 mmol), potassium tert-butoxide (1039.0 mg, 9.26 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (86.4 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (63.6 mg, 0.06 mmol), while continuing to purge with nitrogen. Nitrogen flow was discontinued and the flask was sealed and heated at 90° C. for 8 h. The reaction was cooled and the solvent was removed by rotary evaporation. The resulting residue was suspended in saturated aqueous sodium bicarbonate (10 mL) and extracted with chloroform (4×25 mL). The combined organic extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation to a thick dark mass. This was purified by column chromatography, using methanol/chloroform (2:98, v/v) as the eluent, to afford 0.70 g of the desired compound as a light brown viscous liquid (78.6%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([N:30]4[CH2:33][CH2:32][CH2:31]4)=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:34]=2)[CH:6]=1)(=O)C.CO.C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[OH:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH:19][C:20]([C:22]4[N:26]([CH3:27])[N:25]=[CH:24][C:23]=4[C:28]([N:30]4[CH2:33][CH2:32][CH2:31]4)=[O:29])=[O:21])[CH:16]=[CH:15][N:14]3[CH:34]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)Oc1cccc(-c2cn3ccc(NC(=O)c4c(C(=O)N5CCC5)cnn4C)nc3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2cc(-c3cccc(O)c3)nc2n1
Temperature: 25 °C
Yield: 57.2 %

Procedure:
3-(7-(4-(Azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)imidazo[1,2-a]pyrimidin-2-yl)phenyl acetate (Example 105; 25 mg, 54.4 μmol) was combined with MeOH (0.7 ml), CH2Cl2 (0.2 ml) and H2O to give a yellow solution. NaHCO3 (4.57 mg, 54.4 μmol) was added and the reaction mixture was stirred at RT over night. The precipitated light yellow solid was filtered and washed with MeOH and H2O. After drying over night under high vacuum, the product (13 mg, 56%) was obtained as light yellow solid. MS (m/z)=418.2 [M+H+].
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([S:19]([CH:21]([CH3:23])[CH3:22])=O)=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].[I-].[Na+].F[C:32](F)(F)[C:33](OC(=O)C(F)(F)F)=[O:34]>O1CCCC1>[CH3:32][CH2:33][O:34][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([S:19][CH:21]([CH3:22])[CH3:23])=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(S(=O)C(C)C)c2cc(OCc3ccccc3)ccc2n1C
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(SC(C)C)c2cc(OCc3ccccc3)ccc2n1OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.8 %

Procedure:
A mixture of ethyl 1-methyl-3-[(1-methylethyl)sulfinyl]-5-(phenylmethoxy)-1H-indole-2-carboxylate (0.50 g, 1.3 mmol) and sodium iodide (0.69 g, 4.6 mmol) in 30 mL of tetrahydrofuran is cooled to 0° C. and treated dropwise with trifluoroacetic anhydride (1.0 mL, 1.5 g, 7.1 mmol). The mixture is stirred for 10 minutes, then quenched by pouring into 100 mL of cold 5% aqueous sodium bicarbonate solution. The mixture is extracted with ether, and the combined organic layers are washed with 5% aqueous sodium thiosulfate solution, followed by brine. The organic layer is dried (anhydrous magnesium sulfate) and evaporated to give 0.44 g (92%) of product; mp 94°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:19]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1c1cccc(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1(Cc1ccccc1)c1cccc(Cl)c1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (0.17 g, 0.6 mmol) (from Example 5b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 5 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give two products. Lower Rf sample was recrystallized from dichloromethane-hexanes to give rac-3-benzyl-6-chloro-3-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.17 g, 76.9%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:59][N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][CH:63]5[CH2:64][CH2:65][N:60]([CH3:59])[CH2:61][CH2:62]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:33])([F:34])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-(trifluoromethyl)benzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34-1.67 (m, 9 H) 1.70-1.85 (m, 3 H) 2.13 (br. s., 1 H) 2.27 (s, 3 H) 2.84-2.93 (m, 1 H) 3.32 (s, 3 H) 3.74-3.86 (m, 1 H) 4.00 (t, J=14.0 Hz, 1 H) 4.50 (quin, 1 H) 7.96 (d, J=8.6 Hz, 1 H) 8.12 (dd, 1 H) 8.20 (s, 1 H) 8.21 (s, 1 H) 8.48 (d, J=7.8 Hz, 1 H) 8.52 (s, 1 H). [M+H] calc'd for C27H32F5N7O2, 582; found 582.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=1[C:13]([O:15]C)=O)=O>C(O)(=O)C>[CH3:12][C:9]1[N:8]=[C:7]2[C:13](=[O:15])[NH:2][NH:3][CH:4]=[C:6]2[C:10]=1[CH3:11]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c(=O)[nH][nH]cc-2c1C
Temperature: 110 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
1.50 g (0.030 mole) of hydrazine monohydrate were dropwised added slowly to a solution of 4.00 g (0.022 mole) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate in 80 ml of acetic acid at room temperature and the resulting mixture was stirred at 110° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into ice-water. The resulting precipitates were collected by filtration and washed well with water. The precipitates were dissolved in dichloromethane and the solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 3.40 g of 2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-one as a grayish-white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:15]([NH:17][C:18]3[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O.C(O)C>[CH3:27][C:26]1[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]2[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=2)=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH3:37])=[N:3][N:4]=[CH:5]2
Reactant: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccc2c(Cl)nncc2c1
Reactant: Cc1ccccc1B(O)O
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: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccnn2C)cc1-c1ccc2c(-c3ccccc3C)nncc2c1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with 3-(1-chlorophthalazin-6-yl)-4-methyl-N-(1-methyl-1H-pyrazol-5-yl)benzamide (65 mg, 172 μmol), o-tolylboronic acid (28 mg, 206 μmol), potassium carbonate (31 μl 516 μmol), tetrakis(triphenylphosphine)palladium (20 mg, 17 μmol) and DME:water:ethanol (7:3:2, 2 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 140° C. for 20 mins.
Reaction SMILES: [CH2:1]([CH:10]1[C:15](=O)[CH2:14][CH2:13][S:12](=[O:18])(=[O:17])[CH2:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH3:21].C(O)(=O)C.Cl>O>[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:25]1[C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:10]2[CH2:11][S:12](=[O:18])(=[O:17])[CH2:13][CH2:14][C:15]1=2
Reactant: O=C(CC1CS(=O)(=O)CCC1=O)c1ccccc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCCn1c(-c2ccccc2)cc2c1CCS(=O)(=O)C2

Procedure:
A solution of 2.0 g (0.0075 mole) of 3-phenacyl-2,3,5,6-tetrahydrothiopyran-4-one-1,1-dioxide, 0.85 g of dimethylaminopropylamine and 30 ml. of acetic acid is heated under reflux for 5 hours. The reaction solution is cooled, diluted with water, adjusted to a pH of 1 with hydrochloric acid, and then washed with ether. The solution is made basic with sodium bicarbonate and extracted with ether. The ether extract is dried and concentrated to a solid. The solid is recrystallized from 2-propanol to give off-white needles of 1-(3-dimethylaminopropyl)-2-phenyl-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole-5,5-dioxide, m.p. 123° to 125°C.
Reaction SMILES: [C:1]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:24][C:25]1[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:29]=[C:28]([O:41][CH2:42][CH2:43][CH2:44][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[C:26]=1[NH2:27])[CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:20]([N:24]1[C:25]2[CH:31]=[C:30]([O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:37][CH3:38])[CH2:39][CH3:40])[CH:29]=[C:28]([O:41][CH2:42][CH2:43][CH2:44][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[C:26]=2[N:27]=[C:13]1[C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][C:8]2[CH:18]=[CH:19][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:11]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCNc1cc(OCCCN(CC)CC)cc(OCCCN(CC)CC)c1N
Reactant: CC(C)(C)c1ccc(Oc2cccc(C=O)c2)cc1
Solvent: CCO
Product: CCCCn1c(-c2cccc(Oc3ccc(C(C)(C)C)cc3)c2)nc2c(OCCCN(CC)CC)cc(OCCCN(CC)CC)cc21
Yield: 88.3 %

Procedure:
{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine was formed employing 3(4-t-butyl-phenoxy)benzaldehyde (127 mg; 0.50 mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via General Procedures J1 and J2 and I) (1.6 mg; 0.25 mmol) in ethanol (1 mL) following General Procedure K. The crude product was purified by silica gel column chromatography using 10% MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%) as eluent to afford 145 mg (76%) of {3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[N:13][C:12]=2[N:20]2[CH2:25][CH2:24][CH:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]2)[CH2:5][CH2:4]1.[Cl:33][C:34]1[CH:50]=[CH:49][C:37]([CH2:38][NH:39][C:40]([C:42]2([C:45]([F:48])([F:47])[F:46])[CH2:44][CH2:43]2)=[O:41])=[CH:36][C:35]=1[N:51]=[C:52]=S.CC#N.CC(C)N=C=NC(C)C>CN>[F:32][C:2]([F:1])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[CH:16]=[C:15]3[N:17]=[C:52]([NH:51][C:35]4[CH:36]=[C:37]([CH2:38][NH:39][C:40]([C:42]5([C:45]([F:48])([F:47])[F:46])[CH2:44][CH2:43]5)=[O:41])[CH:49]=[CH:50][C:34]=4[Cl:33])[N:18]([CH3:19])[C:14]3=[N:13][C:12]=2[N:20]2[CH2:25][CH2:24][CH:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]2)=[O:30])[CH2:5][CH2:4]1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Agent: CN
Solvent: CC#N
Product: Cn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CCC(C(F)(F)F)CC3)nc21
Reaction time: 5 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-5-amino-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid amide (110 mg, 0.24 mmol), N-(4-chloro-3-isothiocyanato-benzyl)-1-trifluoromethyl-cyclopropylcarboxamide (prepared according to WO2010/100249; 80 mg, 0.24 mmol) and MeCN (7.5 mL) is stirred for 5 h. Then DIC (50 μl, 0.32 mmol) is added and it is stirred overnight at rt and for 2 h at 60° C. The crude mixture is diluted with 40% aq. methylamine-solution, filtered, concentrated and purified by prep. HPLC (X-bridge C18 column; water (+0.15% aq. Ammonia)/MeOH 9:1->MeOH).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.IC.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:32][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:11]=[C:12]([CH:27]=[CH:28][CH:29]=3)[CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4[nH]ccc4c3)c2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCc1ccc(OCc2cccc(-c3ccc4c(ccn4C)c3)c2)cc1
Yield: 55.4 %

Procedure:
A solution of methyl 3-(4-{[3-(1H-indol-5-yl)benzyl]oxy]phenyl)propanoate (0.40 g, 1.04 mmol), iodomethane (0.18 mL, 2.89 mmol) and potassium carbonate (0.50 g, 3.62 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 4 days. The reaction solution was diluted with ethyl acetate, and the mixture washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-1:3-1:2) to give the title compound (0.23 g, yield 56%) as colorless prism crystals. MS: m/z 400 (MH+).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:23]
Reactant: Cc1ccccc1C(=O)O
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Product: Cc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-methylbenzoic acid. MS (ESI) mass calcd. for C22H22N4O, 358.45; m/z found, 359.2 [M+H]+.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[C:30][P:31](=[O:36])([OH:35])[O:32][CH2:33][CH3:34])=[CH:25][CH:24]=1.[Cl:37][CH2:38][CH2:39][CH2:40][C:41]#[CH:42]>[Au].ClC(Cl)C>[CH2:33]([O:32][P:31]1(=[O:35])[CH:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=2)[CH:42]=[C:41]([CH2:40][CH2:39][CH2:38][Cl:37])[O:36]1)[CH3:34]
Reactant: C#CCCCCl
Reactant: CCOP(=O)(O)C#Cc1ccc(Cl)cc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccc(Cl)cc2)C=C(CCCCl)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen (4-chlorophenyl)ethynylphosphonate (73.4 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, 5-chloropent-1-yne (61.5 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-p-chlorophenyl-6-(3-chloropropyl)-1,2-oxaphosphorin 2-oxide (51.0 mg, 49%) which is a title compound.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][CH:13]2[CH2:14][CH2:15]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].[Cl-].[Li+]>CN(C)C=O>[C:1]1([C:7]([C:8]2[NH:28][N:27]=[N:26][N:9]=2)([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:15][CH2:14][CH:13]2[CH2:19][CH2:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1cccnc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: c1ccc(C(CCN2CC3CCC2CC3)(c2cccnc2)c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 5.69 parts of 2-phenyl-(3-pyridyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile, 1.67 parts of sodium azide, 1.38 parts of ammonium chloride and 0.025 parts of lithium chloride in 30 parts by volume of dimethylformamide was stirred for 12 hours under nitrogen at 120° C. After the reaction time was completed, the material was cooled and filtered. The collected precipitate was washed with dimethylformamide and water. The precipitate was then dissolved in 100 parts by volume of 0.2N NaOH. The resultant solution was filtered. The filtrates were neutralized with dilute hydrochloric acid. The product which separated was recrystallized from ethanol. The procedure afforded 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole.
Reaction SMILES: C([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:27][N:11]1[CH2:12][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CCNCC(NC(=O)c2n[nH]c3ccccc23)C1

Procedure:
N-(1-Benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (850 mg) is dissolved in ethanol (40 ml) and hydrogenerated over 10% palladium on carbon (100 mg) at about 50° C. After the calculated amount of the hydrogen is absorbed, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the title compound as an oil. The free base thus obtained is converted to the oxalate 3/2 hydrate of the title compound in a usual manner, m.p. 163-166° C. (recrystallzed from ethanol-diethyl ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:29][C:30](=[NH:33])[CH2:31][CH3:32].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]2[O:15][N:33]=[C:30]([CH2:31][CH3:32])[N:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCC(=N)NO
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCc1noc(C=Cc2ccc(OC)c(OC)c2)n1
Temperature: 25 °C

Procedure:
3-(3,4-Dimethoxy-phenyl)-acrylic acid (compound of Example 2, Method A, Step 1; 4 g, 19.21 mmol) was dissolved in DMF (30 mL) to which 1,1′-Carbonyldiimidazole (CDI) (4.04 g, 24.97 mmol) was added and the reaction mixture was stirred at room temperature. At the end of 3 h, N-hydroxy-propionamidine (2.03 g, 23.05 mmol) was added and the reaction mixture was stirred at room temperature for 8 h. After completion of the reaction, additional CDI (4.04 g, 24.97 mmol) was added and the reaction mixture was refluxed at 110° C. to 120° C. for 8 h to effect cyclodehydration. After evaporation of DMF, the residue obtained was cooled to room temperature followed by addition of water (25 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (2×10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:14])[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[O:37][CH3:38])[C:21]([Cl:39])=[CH:20][N:19]=1.ClC1C(NC2C=CC(N3CCOCC3)=CC=2OC)=NC(NC2C(=O)N(C)C3C=CC=C(OC)C=3CC2)=NC=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[O:37][CH3:38])=[N:23][C:18]([NH:1][C:2]2[C:7]3[N:8]([CH3:14])[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=3[C:5]([O:15][CH3:16])=[CH:4][CH:3]=2)=[N:19][CH:20]=1
Reactant: COc1ccc(N)c2c1CCCC(=O)N2C
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc(N2CCOCC2)ccc1Nc1nc(NC2CCc3c(OC)cccc3N(C)C2=O)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc(OC)c3c2N(C)C(=O)CCC3)ncc1Cl

Procedure:
Analogous to procedure Example 101b, 9-Amino-6-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (40 mg, 0.182 mmol) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (60 mg, 0.165 mmol) were converted to -[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-6-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (32 mg, 37%), purified by ISCO chromatography. MP: 230-232° C. 1H-NMR (CDCl3) δ 8.15 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.60 (s, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.52 (s, 1H), 6.46 (m, 2H), 3.91 (s, 3H), 3.88 (t, J=4.7 Hz, 4H), 3.85 (s, 3H), 3.16 (s, 3H), 3.14 (t, J=4.6 Hz, 4H), 2.15-2.4 (br m, 5H), 1.84 (br m, 1H); LC/MS (ESI-pos) m/z 539.36 (M+H).