Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:21])[C:16]=1[O:17][CH2:18][CH2:19][CH3:20])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:25]([O:29][CH2:30][CH3:31])(=[O:28])[CH:26]=[CH2:27].[Na+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[CH2:30]([O:29][C:25](=[O:28])[CH2:26][CH2:27][C:12]([C:11]1[CH:14]=[C:15]([I:21])[C:16]([O:17][CH2:18][CH2:19][CH3:20])=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:13])[CH3:31]
Reactant: C=CC(=O)OCC
Reactant: CCCOc1c(I)cc(C=O)cc1OCc1ccccc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1c(I)cc(C(=O)CCC(=O)OCC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.1 %

Procedure:
To a solution of 3-benzyloxy-4-propoxy-5-iodo benzaldehyde (25.5 g, 0.064 mol) in DMF (155 ml) was added sodium cyanide (0.78 g, 0.016 mol) and stirred at room temperature for 45 min under nitrogen atmosphere. Ethyl acrylate (5.21 g, 0.057 mol) in DMF (30 ml) was added slowly and stirred at room temperature for 30-40 mints. Ethyl acetate (185 ml) and 15% NaCl solution were added to the reaction mixture and the two layers were separated. The aqueous phase was extracted with ethyl acetate (250 ml). The combined organic extracts were washed with saturated aqueous NaHCO3 (125 ml) followed by 5% aqueous NaCl (180 ml). The ethyl acetate layer was dried Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using ethyl acetate:light petroleum (1:12) as eluent to give ethyl-4-(3-benzyloxy 4-propoxy-5-iodophenyl)-4-oxo-1-butanoate as a syrup (23.80 g, 74%). TLC: Ethyl acetate:light petroleum (1:9), Rf=0.4; 1H NMR (CDCl3, 200 MHz): δ 1.05 (t, J=7.4 Hz, 3H), 1.3 (t, J=6.97 Hz, 3H) 1.78 (m, 2H), 2.7 (t, J=6.5 Hz, 2H), 3.1 (t, J=6.5 Hz, 2H), 4.06 (t, J=5.6 Hz, 2H), 4.18(q, J=7.1 Hz, 2H), 5.12 (s, 2H), 7.33-7.43 (m, 5H), 7.58 (d, J=1.62 Hz, 1H), 7.97 (d, J=1.62 Hz, 1H); IR (neat): 2970, 2930, 1735, 1690, 1585, 1550 cm−1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[O:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH:12]([NH:17]C(=O)OC)[CH2:11]1.[OH-].[K+]>CO.O>[NH2:17][CH:12]1[CH:13]([CH3:16])[CH2:14][CH2:15][N:10]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH:8]=[O:9])[CH2:11]1
Reactant: COC(=O)NC1CN(c2c(Cl)cccc2C=O)CCC1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CCN(c2c(Cl)cccc2C=O)CC1N
Temperature: 25 °C
Yield: 31.8 %

Procedure:
To a stirred solution of methyl 1-(2-chloro-6-formylphenyl)-4-methylpiperidin-3-ylcarbamate (220 mg, 0.71 mmol) (Method 119) in MeOH (3 ml) was added 40% aqueous solution of KOH (10 ml) drop wise, and the resulting mixture was heated at reflux for 16 h. The mixture was allowed to cool to rt, diluted with water, and extracted with DCM. The combined organic extract was dried over anhydrous Na2SO4, filtered, and conc. in vacuo. The resulting residue was purified via silica gel chromatography (100% ethyl acetate to 10% methanol in ethyl acetate) to yield the title compound as a light yellow gum (0.057 g, 31.9%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1 H), 7.40 (t, 2 H), 7.07 (t, 1 H), 4.29 (d, 1 H), 3.58 (ddd, 1 H), 3.38 (dd, 1 H), 3.11 (td, 1 H), 2.81 (d, 1 H), 2.20-1.91 (m, 1 H), 1.31-1.14 (m, 1 H), 1.08 (d, 3 H), 0.63-0.37 (m, 1 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Sn](CCCC)(CCCC)CCCC.I[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.[Cu]Cl>[CH2:28]([O:27][P:25]([C:24]1[CH:23]=[CH:22][S:21][C:20]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O:30][CH2:31][CH3:32])=[O:26])[CH3:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOP(=O)(OCC)c1ccsc1I
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccsc1-c1cccs1

Procedure:
Copper(I) chloride (2.5 equivalents) was charged into a reaction container, to which 2-thienyltributyl tin (2.5 equivalents) and 2-iodo-3-diethoxyphosphorylthiophene were added under nitrogen atmosphere while being dissolved in tetrahydrofuran, followed by heating under reflux for 20 hours. After completion of the reaction, the reaction solution was filtered through celite and the resulting residue was washed with ethyl acetate. The filtrate was washed three times with a 1N hydrochloric acid aqueous solution and a 10% saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting crude product was purified with a silica gel column (hexane:ethyl acetate=1:3) to obtain a colorless liquid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[S:8]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]#[N:22])=[CH:17][CH:16]=1)([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].C(O)(=O)C.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])(=O)C.[Na+]>O>[S:8]([C:15]1[CH:16]=[CH:17][C:18]([N:21]=[N:22][C:36]2[CH:37]=[CH:38][C:33]([N:32]([CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH3:39])=[CH:34][CH:35]=2)=[CH:19][CH:20]=1)([C:11]([F:13])([F:14])[F:12])(=[O:10])=[O:9]
Reactant: CN(CCCCO)c1ccccc1
Reactant: N#[N+]c1ccc(S(=O)(=O)C(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(CCCCO)c1ccc(N=Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 38.2 g (0.1 mole) of 4-triflylbenzenediazonium hexafluorophosphate in a 50:50 mixture of glacial acetic acid and water at 0° C. is added 17.9 g (0.1 mole) of N-4-hydroxybutyl-N-methylaniline dropwise. The reaction mixture is stirred at 0° C. for 15 minutes, and 12.3 g (0.15 mole) of sodium acetate is added with stirring. The reaction is stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred for 16 hours. Compound C is collected by filtration and purified by recrystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[O:12][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CCCCCCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)OC)cc1Cl
Reaction time: 8 h

Procedure:
Methyl 3,5-dichloro-4-hydroxybenzoate, (173, 0.78 mol), 1-bromododecane (234 g, 0.94 mol) and potassium carbonate (130 g, 0.94 g) in DMF (1000 mL) were heated to 70° C. with good stirring for about 8 hrs. The reaction was cooled and treated with 2N-HCl to neutralize the excess potassium carbonate. The mixture was then extracted with ethyl acetate. The ethyl acetate was washed with 2N-HCl(×3), dried (MgSO4), filtered and concentrated to give an oil. This oil was taken on to the next step without further purification.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[C:8]1([N:14]2[C:22](=[O:23])[C:21]3[C@@H:20]4[C:24]([CH3:26])([CH3:25])[C@@:17]([CH3:27])([CH2:18][CH2:19]4)[C:16]=3[NH:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[CH:3]1([CH2:2][N:15]2[C:16]3[C@:17]4([CH3:27])[C:24]([CH3:26])([CH3:25])[C@@H:20]([CH2:19][CH2:18]4)[C:21]=3[C:22](=[O:23])[N:14]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: ICC1CCCC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccccc2)n1CC1CCCC1
Temperature: 100 °C
Yield: 3.8 %

Procedure:
A mixture of (iodomethyl)cyclopentane (prepared according to W. L. Corbett US 20040067939; 352 mg, 1.68 mmol) and (4R,7S)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 90 mg, 0.34 mmol) was heated in an oil-bath at 100° C. for 6 days. The reaction mixture was allowed to cool and it was then diluted with dichloromethane (200 mL) and washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL). The organic extract was dried (magnesium sulfate), filtered, evaporated, and the residue purified on an Isco 40 g column, eluting with 30-100% ethyl acetate/hexanes and then held under high vacuum to give (4R,7S)-1-(cyclopentyl)methyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (4.5 mg, 4%) as a semi-solid. ES(+)-MS (M+H) 351.
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(O)(=O)=O)=C[CH:2]=1.[C@@H:12]1([N:21]2[C:30]3[N:29]=[CH:28][N:27]=[C:25]([NH2:26])[C:24]=3[N:23]=[CH:22]2)[O:20][C@H:17]([CH2:18][OH:19])[C@@H:15]([OH:16])[C@H:13]1[OH:14].COC(OC)(C)C.[OH-].[NH4+]>CC(C)=O.C(Cl)Cl.C(O)C>[CH3:2][C:1]1([CH3:6])[O:14][C@@H:13]2[C@@H:15]([C@@H:17]([CH2:18][OH:19])[O:20][C@H:12]2[N:21]2[C:30]3[N:29]=[CH:28][N:27]=[C:25]([NH2:26])[C:24]=3[N:23]=[CH:22]2)[O:16]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)OC
Solvent: CCO
Solvent: CC(C)=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(N)ncnc21
Yield: 87.7 %

Procedure:
A solution of p-toluenesulfonic acid (7.79 g, 0.45 mol) in dry acetone (100 ml) is added dropwise to a solution of adenosine (10 g, 0.037 mol) in dry acetone (300 ml). 2,2-Dimethoxypropane (18.18 ml, d=0.847) is then added to the reaction mixture, and the mixture stirred for 48 hours (TLC methylene chloride/ethanol 9:1). The solution slowly becomes clear and is made basic with 3% ammonium hydroxide (800 ml). The solvent is removed at reduced pressure, keeping the temperature below 30° C. until formation of a solid that is collected by filtration. This procedure is repeated several times by concentrating the filtrate. A white solid is obtained (10.08 g, 0.0328 mol, 87.7% yield).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[C:4](=[CH:5][C-:6]=[CH:7][CH:8]=2)[O:3][CH2:2]1.[Mg+2].[Br-].CON(C)[C:16]([C:18]1[C:27](=[O:28])[C:26]2[C:21](=[N:22][C:23]([CH3:29])=[CH:24][CH:25]=2)[N:20]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Br:37])[N:32]=2)[CH:19]=1)=[O:17].[Cl-].[NH4+]>C1COCC1>[Br:37][C:33]1[N:32]=[C:31]([CH2:30][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=3)[C:27](=[O:28])[C:18]([C:16]([C:7]3[CH:6]=[CH:5][C:4]4[O:3][CH2:2][CH2:1][O:10][C:9]=4[CH:8]=3)=[O:17])=[CH:19]2)[CH:36]=[CH:35][CH:34]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C)ccc2c1=O
Reactant: [c-]1ccc2c(c1)OCCO2
Agent: [Br-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1ccc2c(=O)c(C(=O)c3ccc4c(c3)OCCO4)cn(Cc3cccc(Br)n3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
0.896 mL of 3,4-(ethylenedioxy)phenylmagnesium bromide (0.448 mmol, 0.5M in THF) was added to 85 mg (0.204 mmol) of 1-(6-Bromo-pyridin-2-ylmethyl)-7-methyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide dissolved in 1 mL of THF and the reaction was stirred at room temperature for 1 hour. Saturated ammonium chloride was added and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography using 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 38.2 mg of 1-(6-Bromo-pyridin-2-ylmethyl)-3-(2,3-dihydro-benzo[1,4]dioxine-6-carbonyl)-7-methyl-1H-[1,8]naphthyridin-4-one as a white solid. LC-MSD, m/z for C24H18BrN3O4 [M+H]: 492.05 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.4 min
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[N:18][OH:19])=[CH:12][CH:11]=1.[C:25]([C:27]1[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:6][C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:34])=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[O:19][N:18]=2)=[CH:12][CH:11]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccccc2F)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccccc4F)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(2-fluoro-phenoxy)-phenyl)-acetohydroximoyl chloride (210 mg, 0.622 mmol) described in Manufacturing Example 83-1-3 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.225 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (94.1 μL, 0.675 mmol) at room temperature, which was stirred for 16 hours at room temperature. Water was added at room temperature to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (41.7 mg, 49.2%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1([C@H:26]2[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]2)[CH:25]=[CH:24][CH:23]=[N:22]1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:31][C@H:28]2[CH2:29][CH2:30][C@H:26]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[CH2:27]2)[C:3]=1[F:20]
Reactant: N[C@H]1CC[C@H](n2cccn2)C1
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](n4cccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 10.5 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (702 mg, 2.53 mmol), trans-3-(1H-pyrazol-1-yl)cyclopentylamine (460 mg, 3.04 mmol) and di-isopropylethylamine (0.970 mL, 5.57 mmol) in anhydrous DMSO (14 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (Hexane/EtOAc=1/10→EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[trans-3-(1H-pyrazol-1-yl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (108 mg, 10%) as a yellow powder.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5]CCNC)=[O:4].CCN(C(C)C)C(C)C.[CH2:21]([O:28][C:29]([N:31]1[C:35](=O)[CH2:34]C[C:32]1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([O:28][C:29](=[O:30])[N:31]([CH3:32])[CH2:35][CH2:34][NH:5][C:3](=[O:4])[C:2]([F:11])([F:10])[F:1])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CNCCNC(=O)C(F)(F)F
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCNC(=O)C(F)(F)F)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound A (88.2 g, 311 mmol) and DIEA (54.1 mL, 311 mmol) in THF (350 mL) was cooled in an ice bath, followed by the addition of a solution of N-(benzyloxycarbonyl)succinimide (76.6 g, 307 mmol) in THF (150 mL) drop wise over the period of 20 min. The temperature of the reaction mixture was raised to ambient temperature and stirring was continued for an additional 30 min. Solvents were then evaporated and the resulting residue was dissolved in EtOAc (600 mL). The organic layer was extracted with 5% aq. NaHCO3 (2×150 mL) and brine (150 mL). The organic layer was evaporated to provide compound B as yellowish oil. LC-MS [M+H] 305.1 (C13H15F3N2O3+H, calc: 305.3). Compound B was used directly in the next reaction without purification as a MeOH solution.
Reaction SMILES: [Si]([O:18][C:19]1[CH:62]=[CH:61][C:22]([O:23][CH2:24][C@@H:25]([OH:60])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:59]=[CH:58][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH:45](C4C=CC=CC=4)[C:46]4[CH:51]=CC=C[CH:47]=4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH3:47][CH:46]([CH3:51])[CH2:45][CH2:44][NH:43][C:41]([N:38]1[CH2:37][CH2:36][CH:35]([NH:34][C:33]2[CH:58]=[CH:59][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:60])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:62][CH:61]=3)=[CH:31][CH:32]=2)[CH2:40][CH2:39]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCC(c4ccccc4)c4ccccc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)CCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 38.5 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(2,2-diphenylethyl)-1-piperidinecarboxamide (0.194 g, 0.26 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.05 g, 0.10 mmol).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:30]([O:11][CH:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][N:6]=2)[C:2](=[O:1])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: O=C1c2nccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 18.3 %

Procedure:
The procedure is as in Example 7, but starting with 5-hydroxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (6.3 g) in methylene chloride (80 cc), triethylamine (5.05 g), methacryloyl chloride (3.14 g) and 4-dimethylaminopyridine (50 mg). The residue obtained is purified by recrystallization in acetonitrile followed by chromatography on neutral alumina (50 g) contained in a column 1.5 cm in diameter, eluting with methylene chloride and collecting 15-cc fractions. Fractions 12 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 6-(7-Chloro-1,8-naphthyridin-2yl)-7-oxo-6,7-dihydro-5H-pyrrolo [3,4-b]-pyrazin-5yl methacrylate (1.4 g), m.p. 255° C., is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19]>>[CH3:16][CH:17]([CH3:33])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:8][C:7]3[C:2]([CH3:1])=[N:3][C:4]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:5][CH:6]=3)[CH2:29][CH2:28]2)[CH:22]=1)=[O:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1nc(-c2ccccc2)ncc1C=O
Product: Cc1nc(-c2ccccc2)ncc1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 4-methyl-2-phenyl-5-pyrimidinecarbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12]1(=O)OCC[O:13]1.C(OCC)(=O)C.O>C1(C)C=CC=CC=1>[CH2:5]([C@@H:2]1[CH2:3][O:4][C:12](=[O:13])[NH:1]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1OCCO1
Reactant: N[C@@H](CO)Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1N[C@H](Cc2ccccc2)CO1
Yield: 78.2 %

Procedure:
3 g of (R)-(+)-2-amino-3-phenylpropanol and 1.8 g of ethylene carbonate in 50 ml toluene in a round bottom flask equipped with a Dean-Stark trap was refluxed for 24 hrs. The reaction mixture was poured into ethyl acetate/water mixture and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried and concentrated. Kugelrohr distillation at 150°-160° C./0.5 mm Hg provided 2.75 g (75%) of an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.OO.S([O-])(O)=[O:29].[Na+]>CO>[OH:29][N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1
Reactant: O=S([O-])O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCN(O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
Compound 18 (0.35 g, 1.1 mmol) was dissolved in methanol (2.1 mL) and was added with a 31% hydrogen peroxide solution (0.13 g, 1.1 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with sodium hydrogen sulfite (0.1 g, 0.96 mmol), and then the deposited crystals were removed by filtration after confirming the disappearance of hydrogen peroxide using a potassium iodide-starch paper. The solvent of the filtrate was evaporated under reduced pressure, the crude product was purified by preparative silica gel chromatography [amino-modified chemically bound silica gel Chromatorex (registered trademark) NH, Fuji Silysia Chemical Ltd., methanol/chloroform=1/9] to obtain Compound 147 (57 mg, 15%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH:18](=[N:9][CH:10]([CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(N)CC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC)N=Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (2 moles) was added to a solution of the product from step (a) (1 mole) in toluene. When addition was complete, benzaldehyde (1 mole) was added. The mixture was azeotroped until no further water was collected, then cooled to room temperature and filtered. The filtrate was evaporated in vacuo to give the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[NH:16][C:17]([C:19]1[S:27][C:22]2=[N:23][CH:24]=[CH:25][N:26]=[C:21]2[CH:20]=1)=[O:18].[ClH:28].O1CCOCC1>O1CCOCC1>[ClH:28].[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:16][C:17]([C:19]2[S:27][C:22]3=[N:23][CH:24]=[CH:25][N:26]=[C:21]3[CH:20]=2)=[O:18])[CH:4]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1NC(=O)c1cc2nccnc2s1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(N)cc1NC(=O)c1cc2nccnc2s1
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-methyl-3-(thieno[2,3-b]pyrazine-6-carboxamido)phenylcarbamate 28 (5.36 g, 13.94 mmol) in dioxane (20 mL) was added 4N HCl/Dioxane (8.71 mL, 34.9 mmol). The reaction was stirred overnight at 60° C. Evaporated to dryness to give N-(5-amino-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide hydrochloride 29 (4.47 g, 100%). NMR (400 MHz, DMSO-d6) 2.32 (s, 3H), 7.25 (dd, J=8.2 and 2.3 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 8.65 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.90 (d, J=2.3 Hz, 1H), 10.3 (br s, 2H), 10.70 (s, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@H:6]([NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH:7]([CH3:9])[CH3:8])C.[NH3:22]>>[CH2:14]([O:13][C:11]([NH:10][C@H:6]([CH:7]([CH3:9])[CH3:8])[CH2:5][C:4]([NH2:22])=[O:3])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N
Reactant: CCOC(=O)C[C@H](NC(=O)OCc1ccccc1)C(C)C
Product: CC(C)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
2.23 g of 3(S)-benzyloxycarbonylamino-4-methylpentanoic acid ethyl ester and 50 ml of 6N ammonia (in methanol) are stirred for 6 days at 75° C. in a bomb tube. The reaction mixture is concentrated by evaporation and the residue is crystallised from ethyl acetate. The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.20; m.p. 171°-172° C.