Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccccc1Br
Reaction time: 3 h

Procedure:
For 3 hours, 21 g (0.098 mole) of o-bromophenylacetic acid was refluxed in 100 ml of anhydrous benzene and 23.5 g (0.198 mole) of thionyl chloride. After completion of the reaction, benzene and unreacted thionyl chloride were removed by distillation under reduced pressure so that unreacted thionyl chloride was removed as completely as possible.
Reaction SMILES: [H-].[Na+].Cl.[NH:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[N:6]=[CH:5]1.[CH3:15]I>CCOC(C)=O.O>[CH3:15][N:4]1[CH:8]=[C:7]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[N:6]=[CH:5]1
Reactant: CI
Reactant: COC(=O)C=Cc1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C=Cc1cn(C)cn1
Reaction time: 24 h

Procedure:
NaH (0.85 g of a 60% dispersion in oil, 21.2 mmol) was placed in a flask, suspended in hexanes, and allowed to settle. The hexanes was decanted and DMF (50 mL) was added, followed by 35-2 (2 g, 10.6 mmol). After 10 minutes methyl iodide (0.79 mL, 12.7 mmol) was added. After stirring for 24 hr the solution was diluted with EtOAc and H2O and the layers were separated. The water layer was basified to pH 11 with saturated NaHCO3 and extracted with EtOAc and CH2Cl2. The organic layers were combined and evaporated. The residue was chromatographed (5% CH3OH/CHCl3 saturated with NH3) to give 35-3 as a white solid.
Reaction SMILES: C(O)C.O1CCCC1.[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[O:21])=[N:18][CH:19]=1.[BH4-].[Na+]>O>[O:9]1[CH2:13][CH2:12][O:11][CH:10]1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][OH:21])=[N:18][CH:19]=1
Reactant: O=Cc1ccc(C2OCCO2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1ccc(C2OCCO2)cn1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 78.3 %

Procedure:
To an ethanol (20 mL) and tetrahydrofuran (20 mL) solution of 5-[1,3]dioxolan-2-yl-pyridine-2-carbaldehyde (1.73 g, 9.66 mmol) described in Manufacturing Example 154-1-3 was added sodium borohydride (731 mg, 19.3 mmol), which was stirred for 25 minutes at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=1:2) to obtain the title compound (1.37 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1>CCO.C1COCC1.[Pd]>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][C:15]=3[CH3:24])=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:28][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(C#Cc3ccc(OCOC)cc3C)cc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCOC)cc3C)cc12
Reaction time: 24 h

Procedure:
A solution of ethyl 3-(5-amino-2-((4-(methoxymethoxy)-2-methylphenyl)ethynyl)-benzo[f][1,7]naphthyridin-8-yl)propanoate (11) (1.0 equiv.) in EtOH/THF (3:1, 0.16M) was flushed with nitrogen. Then, 10% wt Pd/C (0.20 equiv. by weight) was added. The reaction was flushed with hydrogen (2×) and stirred under a hydrogen balloon. After 24 hours, the reaction was filtered through a pad of celite, washing with 5% MeOH in DCM. The filtrate was checked for the presence of starting material using LCMS. The hydrogenation reaction was repeated until no more of the alkyne starting material or alkene intermediate was detected. The crude product was purified by Combiflash using 0-4% MeOH in DCM to give ethyl 3-(5-amino-2-(4-(methoxymethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (12) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([SH:19])[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[F:20][C:21]([F:39])([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH:34]([CH2:37]Br)[CH2:33][CH2:32]1)[CH:22]([F:28])[O:23][C:24]([F:27])([F:26])[F:25]>CN(C)C=O.CCOCC>[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([S:19][CH2:37][CH:34]2[CH2:35][CH2:36][CH:31]([CH2:30][O:29][C:21]([F:20])([F:39])[CH:22]([F:28])[O:23][C:24]([F:26])([F:27])[F:25])[CH2:32][CH2:33]2)[CH:13]=[N:12]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: FC(OC(F)(F)F)C(F)(F)OCC1CCC(CBr)CC1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)n1ncc(SCC2CCC(COC(F)(F)C(F)OC(F)(F)F)CC2)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a suspension of 0.47 g of potassium carbonate in 10 ml of dimethylformamide, 0.75 g of 2-tert.butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.3 g of 4-(1,1,2-trifluoro-2-trifluoromethoxyethoxy)methyl-cyclohexylmethyl-bromide. Were added it was stirred for 2 hours at room temperature, it was diluted with ether, then it was washed with diluted HCl and brine; it was anhydrified, the solvent was evaporated and the obtained rough product was eluted by silica gel chromatography with hexane/ethyl acetate 98/2. 0.65 g of a mixture of CIS/trans (15/85) product was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:30])=[N:27][CH:28]=[CH:29][C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].C1C(=O)N([I:38])C(=O)C1.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:25]4[C:26]([NH2:30])=[N:27][CH:28]=[C:29]([I:38])[C:24]=4[S:23][CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 272.9 %

Procedure:
To a solution of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (150 mg, 0.389 mmol) in DMF (6.0 mL) cooled in an ice-bath was added NIS (264 mg, 1.174 mmol). The reaction mixture was stirred at room temperature overnight. Water was poured into the mixture, the formed brown solid was filtered, dried to give the product 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodothieno[3,2-c]pyridin-4-amine as a brown solid (581 mg). LCMS (ES) m/z=548.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46](=[O:58])[N:47]([C:55](=[O:57])[CH3:56])[C:48]1[CH:53]=[CH:52][CH:51]=[C:50](Br)[CH:49]=1)([CH3:44])([CH3:43])[CH3:42].BrC1C=C(NC(=O)C)C=CC=1.C(=O)(OC(C)(C)C)OC(C)(C)C.COC(=O)C1C=CC(Br)=CC=1>C(#N)C.CN(C1C=CN=CC=1)C>[C:41]([O:45][C:46](=[O:58])[N:47]([C:55](=[O:57])[CH3:56])[C:48]1[CH:49]=[CH:50][CH:51]=[C:52]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)[CH:53]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(=O)N(C(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: CC(=O)Nc1cccc(Br)c1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(N(C(C)=O)C(=O)OC(C)(C)C)c3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (81 mg) and acetyl-(3-bromo-phenyl)-carbamic acid tert-butyl ester (prepared from N-(3-bromo-phenyl)-acetamide and di-t butyl carbonate in acetonitrile in the presence of DMAP, 94 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of acetyl-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic acid tert-butyl ester was obtained, and then the PMB groups were removed according to Deprotection method 1, to obtain the desired compound (D-45) as a pale yellow powder (5 mg, 8%).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>O1CCOCC1>[C:19]1([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(-c2ccn3c(I)cnc3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccn3c(-c4ccccc4)cnc3c2)cc1

Procedure:
Tetrakis(triphenylphosphoine)palladium(0) (92 mg, 0.080 mmol, 0.050 equiv) was added to a deoxygenated mixture of 4-(3-iodoimidazo[1,2-a]pyridin-7-yl)benzaldehyde (2-4, 555 mg, 1.94 mmol, 1 equiv), phenyl boronic acid (486 mg, 3.99 mmol, 2.50 equiv), and aqueous saturated sodium carbonate solution (2.4 mL, 3.0 equiv) in dioxane (20 mL), and the resulting mixture was heated at reflux for 4 h. Additional tetrakis(triphenylphosphoine)palladium(0) (100 mg, 0.09 mmol, 0.05 equiv), phenyl boronic acid (500 mg, 4.0 mmol, 2.5 equiv), aqueous saturated sodium carbonate solution (2.5 mL, 3.1 equiv), and lithium chloride (200 mg, 5 mmol, 3 equiv) were added and the mixture was heated at reflux for 18 h. The reaction mixture was cooled, then concentrated, and the residue was partitioned between half-saturated aqueous NaCl solution (100 mL) and EtOAc (6×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by reverse-phase liquid chromotography (H2O/CH3CN gradient w/0.1% TFA) to give 4-(3-phenylimidazo[1,2-a]pyridin-7-yl)benzaldehyde (2-5) as a tan solid. LRMS m/z (M+H) Calcd 299.3, found 298.9.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:27][C:26]2[CH:25]=[C:24]([OH:28])[CH:23]=[CH:22][C:21]=2[C@@H:20]2[C@@H:11]1[C@H:12]1[C@@:16]([CH2:18][CH2:19]2)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]1)(=[O:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:28][C:24]1[CH:23]=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:29])[CH2:14][CH2:13]4)[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:27][C:26]=2[CH:25]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Solvent: c1ccncc1
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(OC(C)=O)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12

Procedure:
A solution of 60.4 g of 7α-(5-acetoxypentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one in 300 ml of pyridine is stirred with 150 ml of acetic anhydride for 1 hour at room temperature. Then, it is precipitated with a mixture of ice/water/common salt/hydrochloric acid, taken up with ethyl acetate, washed neutral with sodium bicarbonate and common salt solution, and dried on sodium sulfate and concentrated by evaporation in a vacuum. 63.9 g of 3-acetoxy-7α-(5-acetoxypentyl)-estra-1,3,5(10)-trien-17-one is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14]
Reactant: NCC(=O)N1CCOCC1
Reactant: O=Cc1ccccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CN=Cc1ccccc1F)N1CCOCC1

Procedure:
D 4-[2-(2-Fluorobenzylidaneamino)acetyl]morpholine can be prepared as described in Example 2D, but from 5.3 cm3 of 2-fluorobenzaldehyde, 9.1 g of 4-(2-aminoacetyl)morpholine hydrochloride, 6 g of 4 Å seive and 7 cm3 of triethylamine in 150 cm3 of dichloromethane. After treatment, there are obtained 12 g of 4-[2-(2-fluorobenzylideneamino)acetyl]morpholine in the form of an oil used as is in the subsequent syntheses.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19](O)=[O:20])[N:18]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:17]3[N:18]=[C:14]([CH3:13])[O:15][CH:16]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1nc(C(=O)O)co1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)co1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-methyloxazole-4-carboxylic acid (276 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 4 hours. Next, 2M LiOH.H2O (3 mL) was added, and after 30 minutes water (10 mL) was added. The solid formed was filtered, washed with water (2×5 mL) and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide (165 mg, 56% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.15 (s, 1H), 9.68 (s, 1H), 8.63 (s, 1H), 8.37 (d, 1H), 7.67 (s, 1H), 2.52 (s, 3H); LCMS (APCI+) m/z 338.9, 341.0 (M+H)+, Retention time=3.21 minutes (Method 2).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].[CH3:16][C:17]1[NH:18][C:19]([CH3:39])=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.P(OC#N)(OCC)(OCC)=O>CN(C)C=O.O>[CH3:16][C:17]1[NH:18][C:19]([CH3:39])=[C:20]([C:35]([O:37][CH3:38])=[O:36])[CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:22]=1[C:23]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:24]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: CCOP(=O)(OC#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)N2CCC3(CC2)CC(=O)N(OC)C3=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a solution of of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione.hydrochloride (0.21 g) obtained in Example 9, 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid (0.3 g) and triethylamine (0.26 ml) in dimethylformamide (7 ml) was added dropwise, under ice-cooling, 0.22 ml of diethyl cyano phosphate, and the mixture was stirred for 30 minutes. To the reaction mixture was added water (20 ml), which was stirred at room temperature, followed by extraction with dichloromethane. The dichloromethane solution was dried over anhydrous sodium sulfate. The solvent was then evaporated off under reduced pressure. The residual oily product was subjected to a silica gel column chromatography (eluent, ethyl acetate), and the solvent for the solution containing the desired product was evaporated off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 0.31 g of yellow crystals, m.p. 228° to 230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6]([NH2:11])=[CH:7][C:8]=1[O:9][CH3:10].[F:13][C:14]([F:21])([F:20])[CH:15]([OH:19])[C:16](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:12][C:16]([CH:15]([OH:19])[C:14]([F:21])([F:20])[F:13])=[N:11][C:6]=2[CH:7]=1
Reactant: COc1cc(N)c(N)cc1OC
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2nc(C(O)C(F)(F)F)[nH]c2cc1OC
Temperature: 108 °C

Procedure:
4,5-Dimethoxy-benzene-1,2-diamine (2.02 g; 12.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (2.67 g; 18.5 mmoles) were suspended in 6N HCl (5 mL; 30 mmoles) and water (4 mL) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (40 mL) and with ethyl acetate (40 mL), then sodium bicarbonate (3.84 g; 46.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The extracts were combined, washed with water (30 mL) and brine (40 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude dark orange solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a bright orange solid.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21](S(C4C=CC(C)=CC=4)(=O)=O)[C:18]3=[N:19][CH:20]=2)=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:2]=[O:3].C(N(CC)C(C)C)(C)C.[CH2:51]([N:53]1[CH2:57][CH2:56][CH:55]([OH:58])[CH2:54]1)[CH3:52]>C(Cl)Cl>[CH2:51]([N:53]1[CH2:57][CH2:56][CH:55]([O:58][C:2](=[O:3])[NH:1][C:4]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]4[C:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][CH3:31])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)=[CH:11][C:5]=2[C:6](=[O:7])[N:8]([CH3:9])[CH3:10])[CH2:54]1)[CH3:52]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12
Reactant: CCN1CCC(O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN1CCC(OC(=O)Nc2ccc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc2C(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.4 %

Procedure:
2-Isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (125 mg, 0.22 mmol), N,N-diisopropylethylamine (0.06 mL, 0.34 mmol), 1-ethyl-pyrrolidin-3-ol (253 mg, 2.2 mmol), and methylene chloride (3 mL) were combined and stirred at room temperature for 18 hours. The reaction was concentrated to dryness in vacuo. The crude material was dissolved in a solution of tetrahydrofuran (4 mL) and methanol (1 mL). To the mixture was added 0.2 mL 50% w/v aqueous potassium hydroxide and the combined mixture stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate, and the mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate and concentrated to dryness in vacuo. The crude material was purified by preparative HPLC to give 25 mg (47 μmol, 22%) of {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-carbamic acid 1-ethyl-pyrrolidin-3-yl ester. 1H-NMR (250 MHz, CDCl3) δ 11.93 (s, 1H), 9.10 (s, 1H), 8.64 (d, J=1.9 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.75-7.54 (m, 5H), 7.30 (t, J=7.1 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 5.10-5.02 (m, 1H), 3.82 (s, 3H), 2.97 (s, 3H), 2.93 (s, 3H), 2.77-2.24 (m, 7H), 1.80-1.72 (m, 1H), 1.03 (t, J=7.2 Hz, 3H); MS: m/z 528.3 (M+H+).
Reaction SMILES: C([O:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)(=O)C1C=CC=CC=1>CN>[OH:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2
Reactant: Nc1nc2c(ncn2COCCCOC(=O)c2ccccc2)c(=O)[nH]1
Agent: CN
Product: Nc1nc2c(ncn2COCCCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 9-(3-benzoyloxypropoxymethyl)guanine (0.5 g) and aqueous 45% methylamine (10 ml) was stirred overnight at room temperature. Excess methylamine and water was evaporated at ∠30° C. under reduced pressure and the residue recrystallized from ethanol to give 9-(3-hydroxypropoxymethyl)guanine (0.24 g), m.p. 223° C. (with resolidification), as the 0.1/2 hydrate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[N:13]([O-])=[O:14].[Na+]>C(O)(=O)C.O>[OH:14][N:13]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)c1ccccn1
Yield: 95.2 %

Procedure:
To a stirring solution of ethyl pyridine-2-acetate (12.6 g, 76.3 mmol) in acetic acid (19 mL) at 5° C. was added a solution of sodium nitrite (6.05 g, 87.7 mmol) in water (12 mL) at a rate sufficient to maintain the internal temperature below 15° C. After complete addition and an additional 30 min, an additional 30 mL of water was added. The resulting white precipitate was filtered, washed with water, saturated aqueous NaHCO3, and again with water. The solid was then dried under vacuum to give 14.1 g (95%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[C:9](=[O:21])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:11][C:4]=12.[H-].[Na+].FC(F)CN1[CH2:32][CH2:31][C:30]2(N3C(=O)C(NC4N=CN=C(NC(C5CC5)=O)C=4OC)=CC(C)=C3C(=O)N2)[CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[C:9](=[O:21])[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:11]3([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:4]=12
Reactant: COc1ccc(CN2Cc3c(OC)ccnc3C2=O)cc1
Reactant: COc1c(NC(=O)C2CC2)ncnc1Nc1cc(C)c2n(c1=O)C1(CCN(CC(F)F)CC1)NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)c3nccc(OC)c3C23CCCCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (2, 1.0 mmol, 1 eq) in tetrahydrofuran (25 mL) add sodium hydride (2.5 mmol, 2.5 eq) at 0° C. Stir the mixture for 20 min and then add 1,5-dibromo pentane (3, 1.5 mmol, 1.5 eq) and stir for 8 h. After completion quench the mixture with water at 0° C. and add ethyl acetate. Separate the layer and remove the solvent to get crude. Purify the crude by silica gel column chromatography to afford 4′-methoxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one (4).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH:27]=O)=[C:19]([CH:22]([O:25][CH3:26])[O:23][CH3:24])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].[CH3:29][NH:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:27][N:30]([CH3:31])[CH3:29])=[C:19]([CH:22]([O:23][CH3:24])[O:25][CH3:26])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2C(=O)Nc1ccc(C#N)cn1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN(C)C)CCCN2C(=O)Nc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-6-formyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 36, 25 mg, 0.066 mmol) and dimethylamine (7.9 M in water, 0.017 ml, 0.131 mmol) in DCM (0.5 ml) was added sodium triacetoxyborohydride (27.8 mg, 0.131 mmol). The reaction mixture was stirred at room temperature for 1 h, poured into sat. aq. NaHCO3 and extracted with DCM (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude material was purified by supercritical fluid chromatography (SFC 1, NH2 column) to give the title compound as a colorless solid. (UPLC-MS 3) tR 0.73 min; ESI-MS 411.2 [M+H]+.