Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].C[Si]([N:20]=[N+:21]=[N-:22])(C)C.C1(C)C=CC=CC=1>O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[N:13]1[C:14](=[O:15])[NH:22][N:21]=[N:20]1)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1-n1nn[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
37.1 g of 2,6-diisopropylphenyl isocyanate and 50 ml of trimethylsilyl azide are stirred for 24 hours at +140° C. The mixture is then cooled to room temperature and stirred with 250 ml of toluene and with 250 ml of water. After 1 hour, the phases are separated and the aqueous phase is extracted with toluene. The combined organic phases are extracted four times with 250 ml of 15% sodium hydroxide solution each time, and then the aqueous phases are combined and washed with ether. After acidification with semi-concentrated hydrochloric acid, crude 1-(2,6-diisopropylphenyl)-5-oxo-2-tetrazoline precipitates. This is recrystallised from a mixture of hexane and toluene in a ratio of 10:1. Melting point 177°-178.5°.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:7]1[C:15]2[C:10](=[C:11]([CH2:17][CH3:18])[CH:12]=[C:13]([Br:16])[CH:14]=2)[NH:9][CH:8]=1)=O)C.[BH4-].[Li+]>O1CCCC1>[Br:16][C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH2:17][CH3:18])[CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(CC)cc(Br)cc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cc(Br)cc2c(CCO)c[nH]c12
Temperature: 90 °C

Procedure:
To a solution of (5-bromo-7-ethyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (1.55 g, 4.8 mmol) in tetrahydrofuran at room temperature under nitrogen was dropped a 2.0 M solution of lithium borohydride in tetrahydrofuran. The reaction mixture was heated at 90° C. oil bath for 5 hours. After cooling to room temperature, it was quenched with 5% hydrochloric acid solution until the excess lithium borohydride was destroyed. To the mixture was added saturated sodium bicarbonate solution and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product of 2-(5-bromo-7-ethyl-1H-indol-3-yl)-ethanol, which went to the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:10][C:11]([O:14][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccccc2[N+](=O)[O-])cc1C(=O)OC
Temperature: 100 °C

Procedure:
A mixture of 4-hydroxyphthalic acid dimethyl ester (1.23 g, 5.95 mmol), o-fluoronitro-benzene (0.81 ml, 7.64 mmol), and potassium carbonate (1.66 g, 12 mmol) in dry DMF (25 ml) was heated at 100° C. for 1 hour. The mixture was cooled to room temperature, filtered and the filtrate evaporated to dryness in vacuo to give 4-(2-nitrophenoxy)phthalic acid dimethyl ester as a yellow oil (yield: 1.97 g, (100%)). 1H—NMR (CDCl3) in ppm: δ 3.9 (6H, 2xs); 7.1-7.2 (2H,m); 7.2 (1H,d); 7.3-7.4 (1H,m); 7.6-7.7 (1H,m); 7.84 (1H,d); 8.03 (1H, d.d.).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].[F:25][C:26]1[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29].COC(C)(C)C>CN(C)C=O>[F:25][C:26]1[CH:33]=[C:32]([O:34][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH3:18])[CH:31]=[CH:30][C:27]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(O)cc1F
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.3 %

Procedure:
560 mg of 5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole were dissolved in 10 ml dimethylformamide. 1.2 g of cesium carbonate and 395 mg 2-Fluoro-4-hydroxybenzonitrile was added and the mixture was stirred at room temperature for three hours. Then 50 ml of methyl-tert-butylether was added, the mixture washed with brine and dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 153 mg of 2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzonitrile as amorphous lyophilisate.
Reaction SMILES: C=[C:2]1[C:17]2[C:9](=[CH:10][C:11]3[O:12][CH2:13][O:14][C:15]=3[CH:16]=2)[CH:8]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)[C@H:7]2[C@@H:3]1[CH2:4][O:5][C:6]2=[O:30].C[N+]1([O-])CC[O:35]CC1>ClCCl.[Os](=O)(=O)(=O)=O>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([CH:8]2[C:9]3[C:17](=[CH:16][C:15]4[O:14][CH2:13][O:12][C:11]=4[CH:10]=3)[C:2](=[O:35])[C@@H:3]3[C@H:7]2[C:6](=[O:30])[O:5][CH2:4]3)[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1c2cc3c(cc2C(c2cc(OC)c(OC)c(OC)c2)[C@@H]2C(=O)OC[C@H]12)OCO3
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Product: COc1cc(C2c3cc4c(cc3C(=O)[C@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC
Temperature: 25 °C
Yield: 125.2 %

Procedure:
(11S,15S)-16-Methylidene-10-(3,4,5-trimethoxyphenyl)-4,6,13-trioxatetracyclo[7.7.0.0^{3,7}.0^{11,15}]hexadeca-1,3(7),8-trien-12-one obtained in Example 1 (0.730 g, 1.22 mmol) and N-methyl morpholine oxide (50 wt-% solution in water, 1.25. mL, 5.34 mmol) were suspended in dichloromethane (60 mL). Osmium tetroxide (4 wt-% solution in water, 0.37 mL, 0.060 mmol) was added to the suspension. The mixture was stirred vigorously at rt. After most of starting material had been consumed (over week-end), NalO4 (0.52 g, 2.44 mmol) was added and the reaction was stirred for an additional 30 min. The reaction was quenched by addition of aqueous sodium thiosulfate (50 mL) and the phases were separated. The aqueous phase was extracted with dichloromethane (2×50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give 630 mg (85% yield) of the product in 75% purity. Another batch of ketone has been purified by filtration through a pad of silica topped with celite and eluting with Heptane:EtOAc 1:1. LCMS: ACE 3 C8, 50×3.0 mm, 10% to 97% acetonitrile in 0.1% TFA in water, 1 mL/min; Rt=2.091.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([O:23]C(=O)C(C)(C)C)[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2].C(O[C:35]([N:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][C:46]([C:49](O)=O)=[CH:45][CH:44]=2)[CH2:39][CH2:38]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:49][C:46]1[CH:45]=[CH:44][C:43]([CH:40]2[CH2:39][CH2:38][N:37]([CH3:35])[CH2:42][CH2:41]2)=[CH:48][CH:47]=1)[C:4]1[C:5]([CH:13]2[CH2:22][CH2:21][C:20]3[CH:19]=[C:18]([OH:23])[CH:17]=[CH:16][C:15]=3[CH2:14]2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCNc1cc2c(cc1C1CCc3cc(OC(=O)C(C)(C)C)ccc3C1)OCO2
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc2c(cc1C1CCc3cc(O)ccc3C1)OCO2
Yield: 69.4 %

Procedure:
Synthesized from pivalic acid 6-(6-ethylaminobenzo[1,3]dioxol-5-yl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (60 mg) according to an analogous synthetic method to Example 337 described below, the title compound (35 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)Cn1nnc2ccccc21

Procedure:
Using general procedure 4 and purification method E with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.25 g, 0.95 mmol) and 1,2,3-benzotriazole (0.136 g, 1.14 mmol) gives the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1>[Pd].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(C#N)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cccc(C#N)c1
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 3-(3-cyano-phenyl)-acrylic acid methyl ester (3.24 g, 17.31 mmol), prepared in Step B of Preparation 44, and palladium on carbon (10%, 0.600 g) in EtOAc (30 mL) was hydrogenated at 25 psi in a Parr shaker for 1 h. The catalyst was removed via filtration through Celite and the solution was concentrated in vacuo. Medium pressure chromatography (6:1 hexanes:EtOAc) provided the title compound of Step A as a clear oil (2.98 g). 1H NMR (400 MHz, CDCl3) δ 7.50-7.36 (m, 4H), 3.65 (s, 3H), 2.97 (t, 2H), 2.63 (t, 2H); MS 190 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[N:10]2[CH2:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43]CC)=[O:42])=[CH:35][CH:34]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:41](/[CH:40]=[CH:39]/[C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:10]2[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=3)[C:11]2=[O:31])=[CH:34][CH:35]=1)([OH:43])=[O:42]
Reactant: CCOC(=O)/C=C/c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)N(Cc2ccc(/C=C/C(=O)O)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
A stirred solution of ethyl 4-(4-cyanophenyl)-3-{4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]benzyl}-6-methyl-l-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 40) (100 mg, 0.16 mmol) in ethanol (2 ml) is treated with 10% aq. sodium hydroxide solution (1 ml). After 16 hours, the pH of the reaction solution is adjusted to 2 with 1 N hydrochloric acid, and the crude product is extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH:16]=O)[CH:5]=2)[CH2:3][CH2:2]1.[N:18]1([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH2:16][N:21]3[CH2:20][CH2:19][N:18]([C:24]4[CH:25]=[CH:26][C:27]([C:28]#[N:29])=[CH:30][CH:31]=4)[CH2:23][CH2:22]3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Product: CC1Oc2c(cc(CN3CCN(c4ccc(C#N)cc4)CC3)cc2C2CC2)NC1=O

Procedure:
Using 346A and 4-(piperazin-1-yl)benzonitrile in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.71 (m, 2H) 0.85-0.96 (m, 2H) 1.42 (d, J=6.82 Hz, 3H) 2.05-2.12 (m, 1H) 2.38-2.48 (m, 4H) 3.27-3.32 (m, 4H) 3.36 (s, 2H) 4.64 (q, J=6.74 Hz, 1H) 6.41 (d, J=1.52 Hz, 1H) 6.68 (d, J=1.77 Hz, 1H) 7.00 (m, J=9.09 Hz, 2H) 7.57 (m, 2H) 10.56 (br. s., 1H). ESI-MS: m/z 403.4 (M+H)+. mp=194.3-195.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[C:21]([C:25]1[O:29]C(=O)[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33](F)[N:32]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:33]4[N:32]=[C:31]([NH:27][NH:26][C:25](=[O:29])[C:21]([CH3:23])([CH3:22])[CH3:24])[CH:36]=[CH:35][CH:34]=4)=[CH:16][CH:15]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: CC(C)(C)c1nn(-c2cccc(F)n2)c(=O)o1
Reactant: Oc1ccc(CCNc2ncnc3scc(Cl)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NNc1cccc(Oc2ccc(CCNc3ncnc4scc(Cl)c34)cc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
To a solution of 4-{2-[(5-chlorothieno[2,3-d]pyrimidin-4-yl)amino]ethyl}phenol (0.152 g, 0.5 mmol) and 5-(tert-butyl)-3-(6-fluoropyridin-2-yl)-3H-[1,3,4]oxadiazol-2-one (0.119 g, 0.5 mmol) in anhydrous DMF (4 mL) was added 60 percent sodium hydride in mineral oil (30 mg, 0.75 mmol) portionwise. The mixture was then stirred at 100° C. overnight. After cooling the reaction was quenched with methanol. The solvent was removed in vacuo and the residue was triturated in CH2Cl2 and water. The organic phase was separated, dried over anhydrous Na2SO4, filtered, concentrated, and purified on preparative HPLC to give the decarboxylated product as a brownish foam, 16 mg, 0.03 mmol, 6.5 percent yield.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:45])[NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:26]=[CH:25][C:24]([CH2:27][N:28]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])C(=O)OC(C)(C)C)=[CH:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:6][C:7]2[CH:43]=[CH:42][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH:22]=[CH:23][C:24]([CH2:27][NH:28][CH2:36][CH2:37][S:38]([CH3:41])(=[O:39])=[O:40])=[CH:25][N:26]=5)[S:20][C:13]=34)=[C:9]([F:44])[CH:8]=2)=[O:45])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
To a solution of 99 (120 mg, 0.18 mmol) in DCM (20 mL) was added TFA (5.6 mL). The reaction mixture was stirred at RT overnight, concentrated, diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 20/80 over 20 CV), to afford the title compound 100 (90 mg, 0.13 mmol, 72% yield, TFA salt) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) δ 8.74 (s, 1H), 8.60 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 7.20 (d, J=10.0 Hz, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.61 (s, 1H), 3.84 (s, 2H), 3.35-3.25 (m, 2H), 3.05 (s, 3H), 3.02-2.90 (m, 2H), 2.59-2.50 (m, 1H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 556.5 (M+H).
Reaction SMILES: C(O)C.C([O:8][C:9](=O)[CH2:10][CH2:11][N:12]([C:16]1[C:21]([NH2:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=1)[CH:13]([CH3:15])[CH3:14])(C)(C)C>C(O)(=O)C>[Cl:23][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:9](=[O:8])[CH2:10][CH2:11][N:12]([CH:13]([CH3:15])[CH3:14])[C:16]=2[N:17]=1
Reactant: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)N1CCC(=O)Nc2cnc(Cl)nc21
Yield: 79.4 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 1.4 g of the 3-[(5-amino-2-chloro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (V-43), prepared in the previous step, was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, water and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 0.85 g of 2-chloro-9-isopropyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-43).
Reaction SMILES: N1C=CN=C1.[CH2:6]=[CH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH:11]=[CH2:12].[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>O>[CH:14]([Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[O:13][CH:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][CH:7]=[CH2:6])([CH3:16])[CH3:15]
Reactant: C=CCC(O)CC=C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Product: C=CCC(CC=C)O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 46 %

Procedure:
There was supplied 1.35 g of imidazole manufactured by Wako Pure Chemical Industries, Ltd. to a 50 mL-Schlenk tube, and thereto, 10 mL of anhydrous N,N-dimethylformaide manufactured by Wako Pure Chemical Industries, Ltd., and 1.2 mL of 1,6-heptadien-4-ol manufactured by Aldrich Chemical Company were added. The obtained mixture was cooled down to 0° C. To the mixture, 1.93 mL of triisopropylsilyl chloride manufactured by Tokyo Chemical Industry Co., Ltd. was added, and the resultant mixture was stirred for 85 hours at a room temperature. Then, an excess amount of water was added thereto, thereby terminating the reaction. A product contained in the reaction mixture was extracted with hexane, and the obtained organic extract was dried over anhydrous sodium sulfate manufactured by Nacalai Tesque, Inc. The dried hexane solution was distilled in vacuo, thereby obtaining 1.1 g (yield: 46%) of 4-(triisopropylsiloxy)-1,6-heptadiene at 93° C. under 21 mmHg as clear colorless oil.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[CH3:23]COC(C)=O>C1COCC1>[C:1]([N:8]([C@@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:23])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(S)-2-(N-Boc-N-Methylamino)-1-(-tert-butyldimethylsilyloxy)-but-3-yne was synthesized according to Method Y above by the treatment of (S)-N-Boc-2-amino-1-(-tert-butyldimethylsilyloxy)-but-3-yne (190 mg, 0.64 mmol) (Example 115B) with NaH (18 mg, 0.76 mmol) and Mel (180 mg, 1.27 mmol) in THF (5 mL). The product was obtained after silica gel column chromatography with a 0-10% EtOAc in hexanes gradient. (Yield 190 mg, 95%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[C:21]([CH:23]5[CH2:25][CH2:24]5)[N:20]([CH3:26])[C:19]=4[CH:27]=3)[C:11](=[O:28])[CH:10]=2)[N:6]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].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.O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:5]5[N:6]=[C:2]([CH:29]6[CH2:31][CH2:30]6)[S:3][CH:4]=5)=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:25][CH2:24]1
Reactant: OB(O)C1CC1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Br)n4)cc3=O)cc21
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: O
Solvent: COCCOC
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(C5CC5)n4)cc3=O)cc21
Temperature: 150 °C
Yield: 24.7 %

Procedure:
A mixture of 4-((2-bromo-1,3-thiazol-4-yl)methoxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (54 mg), cyclopropylboronic acid (30.4 mg), tetrakis(triphenylphosphine)palladium (6.8 mg), potassium carbonate (65.3 mg), DME (1.5 ml) and water (0.5 ml) was heated at 150° C. for 20 min under microwave irradiation. The reaction mixture was then cooled to room temperature, poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (12.2 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[C:15]3[C:31](=[O:38])[C:32]4[CH:33]=[CH:34][N:35]=[CH:36][C:37]=4[C:13]([C:14]=23)=[N:12]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3CCNC(=O)OC(C)(C)C)-c3cnccc3C(=O)c24)cc1
Reactant: CN(C)CCN
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyloxy) isoquino[8,7,6-cd]indazole-6(2H)-one (0.056 g) and 2-(dimethylamino)ethylamine (0.080 mL) in dry pyridine (0.50 mL) is heated at 80° C. The dark solution obtained is held at this temperature for 1 hour, then it is left at room temperature overnight. The dark precipitate obtained is separated by suction and purified by column chromatography (SiO2 ; eluant ethyl acetate and then methylene chloride/methanol 9/0.5 v/v) to give 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-[[2-(dimethylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.024 g) as a red-orange solid.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.CN(C)P(N(C)C)(N(C)C)=O.Cl[CH2:25][C:26]([NH2:28])=[O:27]>CS(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:25][C:26](=[O:27])[NH2:28])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: NC(=O)CCl
Agent: [K]
Solvent: CS(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: NC(=O)COC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
The potassium salt of 4-hydroxyphenylacetic acid (9.5 g, 0.1 mol) was taken up in a mixture of dimethylsulfoxide (80 mL) and hexamethylphosphoramide (5.37 g, 0.1 mol). 2--Chloroacetamide (13.5 g, 0.3 mol) was added and the reaction mixture was first stirred at room temperature for 24 hours, then heated for 1 hour. The reaction mixture was evaporated, then cooled. The product which separated was taken up in ethyl acetate (150 mL), stirred, filtered and evaporated. The oily residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to give the desired ester, carbamoylmethyl 4-hydroxyphenylacetate, melting at 85°-87° C., in 48.8% yield.