Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:23][C:24]1[N:28](C(OC(C)(C)C)=O)[N:27]=[C:26]([O:36][CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[CH:39]=2)[CH:25]=1.N1C=CC=CC=1.Cl>C1COCC1.O1CCOCC1>[CH3:45][O:44][C:42]1[CH:43]=[C:38]([CH2:37][O:36][C:26]2[NH:27][N:28]=[C:24]([NH:23][C:17](=[O:19])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:15]=3)[CH:25]=2)[CH:39]=[C:40]([O:46][CH3:47])[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COc1cc(COc2cc(NC(=O)c3cccc(N4CCNCC4)c3)n[nH]2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.6 %

Procedure:
1-Chloro-N,N-2-trimethyl-1-propenylamine (78 μl, 0.588 mmol, 1.2 eq) was added dropwise to a stirred solution of 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]benzoic acid (150 mg, 0.588 mmol, 1.2 eq) in THF (10 ml) under nitrogen. The mixture was stirred at room temperature overnight. tert-Butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (172 mg, 0.490 mmol, 1 eq) and pyridine (48 μl, 0.588 mol, 1.2 eq) were added and the mixture was heated at 65° C. overnight. The mixture was allowed to cool to room temperature and 4M HCl in dioxane (2 ml) was added. Stirring was continued at room temperature overnight. The precipitated yellow solid was collected by filtration and washed with THF. The solid was triturated with aq NaHCO3 (4 ml) and DCM (2 ml). A small amount of a brown gum remained out of solution. The gum was collected by filtration and washed with water and ether. The aqueous filtrate was extracted with ethyl acetate (3×10 ml) and the combined extracts were dried over MgSO4, filtered and evaporated. The extracted product was combined with the gum from filtration and purified by silica column chromatography, eluting with a gradient of 10-12% MeOH in DCM. Product fractions were evaporated to give the title compound as a white solid (27 mg, 10% yield); 1H NMR (399.902 MHz, DMSO+d4-AcOD) δ 3.13-3.21 (m, 4H), 3.33-3.40 (m, 4H), 3.68 (s, 6H), 5.02 (s, 2H), 5.71 (s, 1H), 6.38 (t, 1H), 6.52 (d, 2H), 7.12-7.17 (m, 1H), 7.33 (t, 1H), 7.37-7.41 (m, 1H), 7.46-7.49 (m, 1H). MS: m/z 438 (MH+)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1.[CH:16]1([CH:19]=[CH:20][C:21]#[N:22])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([CH:19]([CH:16]3[CH2:18][CH2:17]3)[CH2:20][C:21]#[N:22])[CH:9]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1
Reactant: Clc1cc2nccn2c(-c2cn[nH]c2)n1
Reactant: N#CC=CC1CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 7-chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.107 g, 0.4872 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.3403 g, 3.654 mmol) in 2 mL of acetonitrile was added DBU (0.1457 mL, 0.9744 mmol). The reaction mixture was sealed and heated to 50° C. and stirred overnight. To the reaction mixture was added more 3-cyclopropylacrylonitrile (0.100 g, 0.107 mmol) and DBU (0.072 mL, 0.448 mmol) and the reaction mixture was sealed and heated to 60° C. for 4 hours. The reaction mixture was loaded onto directly onto a column of silica gel and eluted with a gradient of 50-75% ethyl acetate in hexanes with 0.5% ammonium hydroxide to afford the title compound (0.119 g, 0.3729 mmol, 76.54% yield). MS (apci) m/z=313.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][CH2:14]OCl.C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: COCOCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc([N+](=O)[O-])cc1Cl

Procedure:
To a solution of 2-chloro-4-nitrophenol (5.2 g) in N,N-dimethylformamide (50 ml) were successively added methoxymethoxy chloride (2.7 ml) and triethylamine (5.0 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to afford 3-chloro-4-methoxymethoxynitrobenzene (8.1 g) as a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:38])([F:37])[F:36])[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:23]([C:22]1[C:17]([NH:16][CH2:15][C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:10][CH2:11]2)=[N:18][C:19]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:38])([F:37])[F:36])=[N:20][CH:21]=1)([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)CNC1CCC(CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reaction time: 16 h

Procedure:
To a solution of (4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexylamino)-acetic acid tert-butyl ester (60 mg, 0.108 mmol) in DCM (1 mL) was added TFA (1 mL). The solution was allowed to stand at room temperature for 16 h before the solvent was removed in vacuo. The residue was taken up in water (1 mL) and 2 N NaOH added until the mixture reached pH 5. The mixture was diluted with water (3 mL) and filtered. The filtered solid was washed with water and Et2O before drying in vacuo to afford the target compound (46 mg, 85%) as a white solid, m/z 499 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][SH:16].[Na].O>CN(C)C=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1SC
Reaction time: 0.5 h

Procedure:
To a solution of 10.02 g of methyl 2-chloro-5-nitrobenzoate dissolved in 100 ml of N,N-dimethylformamide, was added 23.92 g of a 15% aqueous solution of sodium methylmercaptan dropwise under ice cooling. The mixture was stirred for 30 minutes. Water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over anhydrous magnesium sulfate. The crude product obtained by removal of the solvent under reduced pressure was recrystallized from ethyl acetate—hexane, to yield 8.76 g of methyl 2-methylthio-5-nitrobenzoate (melting point: 126.5-127.5° C.) (Reaction Scheme (42) described below).
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[C:6]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH3:32])=[CH:27][CH:26]=2)=[CH:7][C:8](=[O:24])[N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([O:16]CC)=[O:15])[CH:10]=1.Cl>C1COCC1.O>[F:4][C:5]1[C:6]([C:25]2[CH:26]=[CH:27][C:28]([S:31][CH3:32])=[CH:29][CH:30]=2)=[CH:7][C:8](=[O:24])[N:9]([CH2:11][CH2:12][C@@:13]([CH3:23])([S:19]([CH3:22])(=[O:21])=[O:20])[C:14]([OH:16])=[O:15])[CH:10]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(-c2ccc(SC)cc2)cc1=O)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)O)S(C)(=O)=O)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Lithium hydroxide monohydrate (165 mg, 6.68 mmol) was added to a solution of ethyl (2R)-4-{5-fluoro-4-[4-(methylthio)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)butanoate (0.492 g, 1.12 mmol) in THF:water (1:1, 14 mL) and the reaction was allowed to stir at rt for 18 h. The reaction mixture was acidified using 4 M aq HCl to afford a precipitate. The solid was collected via filtration and dried under vacuum to afford the title compound as a solid (339 mg, 73%). MS (LCMS) m/z 414.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3H) 2.17 (ddd, J=13.42, 10.00, 5.07 Hz, 1H) 2.41-2.45 (m, 1H) 2.49 (s, 3H), 3.14 (s, 3H) 3.78-4.15 (m, 2H) 6.46 (d, J=7.81 Hz, 1H) 7.28-7.39 (m, 2H) 7.43-7.55 (m, 2H) 8.01 (d, J=6.83 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22](OC(C)(C)C)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38](C(O)=O)=[CH:37]2.CCN=C=NCCCN(C)C>O1CCOCC1.CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:21]([C:22]([C:38]3[NH:39][C:40]4[C:36]([CH:37]=3)=[CH:35][C:34]([O:33][CH3:32])=[CH:42][CH:41]=4)=[O:23])[CH2:20][CH:19]([CH2:29][Cl:30])[C:12]2=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc(OCc1ccccc1)c1ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(OCc3ccccc3)c3ncccc43)cc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A suspension of 14 (0.10 g, 0.24 mmol) in dioxane (15 mL) was saturated with HCl, stirred at r.t. for 5 h and evaporated. 5-Methoxy-1-H-indole-2-carboxylic acid (0.054 g, 0.28 mmol), EDCI (0.23 g, 1.17 mmol) and DMA (5 mL) were added to the remaining yellow solid, and the red mixture was stirred at r.t. for 52 h. The mixture was partitioned between CH2Cl2 and cold 5% KHCO3 solution. The aqueous layer was extracted with CH2Cl2 (×3). The CH2Cl2 extracts were dried (brine, Na2SO4). Flash chromatography (EtOAc/petroleum ether, 7:3) gave 5-(benzyloxy)-1-(chloromethyl)-3-[(5-methoxy-1H-indol-2-yl)carbonyl]-2,3-dihydro-1H-pyrrolo[3,2-f]quinoline (17d) (0.11 g, 98%) as a yellow solid: mp 186–189° C.; 1H NMR (CDCl3) δ 9.55 (s, 1 H), 8.88 (dd, J=4.2, 1.7, 1 H), 8.37 (s, 1 H), 7.99 (dd, J=8.3, 1.6, 1 H), 7.56 (d, J=7.3, 2 H), 7.42 (dd, J=8.3, 4.1, 1 H), 7.33 (m, 4 H), 7.10 (d, J=2.3, 1 H), 6.99 (m, 2 H), 5.48 (d, J=12.5, 1 H), 5.42 (d, J=12.6, 1 H), 4.74 (dd, J=10.9, 2.0, 1 H), 4.61 (dd, J=10.6, 8.7, 1 H), 4.05 (m, 1 H), 3.85 (s, 3 H), 3.84 (dd, J=11.2, 4.1, 1 H), 3.45 (dd, J=11.0, 10.5, 1 H); 13C NMR (CDCl3) δ 160.7, 155.4, 154.7, 147.9, 142.4, 138.4, 136.4, 131.4, 130.5, 130.2, 128.6, 128.2, 128.0, 127.7, 125.2, 122.4, 117.0, 115.4, 112.7, 106.2, 102.5, 102.4, 70.9, 55.7, 55.2, 45.9, 42.6.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][C:10]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:11]=1[C:12]([OH:14])=O)(=[O:8])[CH3:7].[NH2:20][C:21]1[S:22][C:23]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:25]=1.Cl>O1CCCC1.N1C=CC=CC=1>[C:6]([O:9][C:10]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:11]=1[C:12]([NH:20][C:21]1[S:22][C:23]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([C:26]([CH3:29])([CH3:27])[CH3:28])[N:25]=1)=[O:14])(=[O:8])[CH3:7]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)O
Reactant: CC(C)(C)c1nc(N)sc1N1CCCCC1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)c(N2CCCCC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Under argon atmosphere, phosphorus oxychloride (46 μl, 0.50 mmol) was added to a mixture of 2-acetoxy-5-bromobenzoic acid (90.3 mg, 0.35 mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole (80.7 mg, 0.34 mmol), pyridine (0.1 mL) and tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (84.3 mg) as a crude product.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:6])[NH2:5])#[N:2].[P:7](=[O:11])([OH:10])([OH:9])[OH:8]>O>[P:7]([OH:11])([OH:10])([OH:9])=[O:8].[C:4]([NH:3][C:1]([NH2:2])=[O:8])(=[NH:6])[NH2:5]
Reactant: N#CN=C(N)N
Agent: O=P(O)(O)O
Solvent: O
Product: N=C(N)NC(N)=O

Procedure:
In a preferred method, Oberley '010 reacts dicyandiamide with phosphoric acid for 35 to 45 minutes in water to form guanylurea phosphate (GUP), in a solution that contains 50-70 percent solids. The reaction is only allowed to proceed to about 80-95 percent completion, in order to prevent the formation of insoluble precipitates. Boric acid is then mixed with the GUP solution, and the mixture cooled to ambient temperature and diluted to from 3 to 18 percent solids.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cc(C(=O)O)ccc1C
Yield: 104.7 %

Procedure:
In a similar manner to Step 1 of Example 347, 3-hydroxy-4-methylbenzoic acid (2.00 g, 13.1 mmol) was suspended in dichloromethane (50 mL), and the suspension was treated with diisopropylethylamine (13.7 mL, 78.6 mmol) and chloromethyl methyl ether (5.00 mL, 65.8 mmol). The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (50 mL), and the solution was treated with 2 mol/L aqueous potassium hydroxide solution (50 mL). The solvent was evaporated under reduced pressure. The residue was added with 4 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 3-methoxymethoxy-4-methylbenzoic acid (2.69 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>C1COCC1.CO>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][C:13]([OH:16])([C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1CCN(C(=O)c2cccc(Br)n2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1cccc(Br)n1)N1CCC(O)(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 13 h
Yield: 96.3 %

Procedure:
After 1-(6-bromopicolinoyl)piperidin-4-one (100 mg, 0.353 mmol) was dissolved in THF (1.5 ml), trimethyl(trifluoromethyl)silane (0.5M solution in THF, 1.4 ml, 0.706 mmol) and tetrabutylammonium fluoride (1.0M solution in THF, 0.74 ml, 0.741 mmol) were sequentially added thereto at 0° C., and then the resulting mixture was stirred at room temperature for 13 hours. A saturated aqueous ammonium chloride solution (0.6 ml) was added to the resulting reaction liquid, and then the resulting mixture was stirred for 10 minutes, followed by extraction with MC (10 ml×2). The organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (3% MeOH/MC), to obtain 120 mg of white solid (97%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1.[H][H]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccn1
Solvent: CCO
Product: Nc1cccnc1Nc1ccccn1
Yield: 100.2 %

Procedure:
A solution of 18.3 g of the product of Step A in 550 ml of 95% ethanol containing 1.6 g of 10% palladized carbon was hydrogenated at atmosphere pressure at room temperature until 6.3 liters of hydrogen were absorbed (about one hour) and the mixture was filtered to remove the catalyst. The filtrate was evaporated to dryness under reduced pressure and the 15.8 g of residue (98.6% yield) which was easily changed in air was used for the next step immediately.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1.Cl.S(Cl)(Cl)=O.[NH3:16]>C(OCC)C.C1C=CC=CC=1.CO>[NH2:16][CH2:2][C:3]1[CH:4]=[C:5]([C:9]#[N:10])[CH:6]=[N:7][CH:8]=1
Reactant: N
Reactant: N#Cc1cncc(CO)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: CO
Solvent: CCOCC
Product: N#Cc1cncc(CN)c1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 64 %

Procedure:
A solution of 5-hydroxymethyl-3-pyridinecarbonitrile (4.39 g, 32.7 mmol) in diethyl ether (250 mL) at 23° C. was saturated with gaseous HCl. Solvent was then removed in vacuo and the residue was suspended in thionyl chloride (14.3 mL, 196 mmol). The mixture was then heated at reflux for 2 hours, cooled to 23° C., and diluted with benzene (150 mL). The tan precipitate was isolated by filtration, transferred to a pressure reactor, and dissolved in methanol (30 mL). The methanolic solution was saturated with gaseous ammonia, sealed in the reaction vessel, and heated with stirring at 80° C. for 2.5 hours. After cooling to 23° C., the solution was again saturated with gaseous ammonia, sealed in the vessel, and heated at 80° C. for 5 hours. The reaction mixture was then concentrated in vacuo, and the residue was diluted with aqueous 0.5M NaOH (60 mL). The aqueous layer was extracted with chloroform (3×60 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo to provide 5-aminomethyl-3-pyridinecarbonitrile (2.79 g, 21.0 mmol, 64% yield): Rf 0.19 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 200 MHz)δ8.88 (dd, J=7,2 Hz, 1H), 8.79 (m, 1H), 8.25 (d, J=7 Hz), 3.75 (s, 2H), 2.8 (br s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[C:26]([F:32])=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=2[F:32])=[N:3][CH:4]=1
Reactant: Oc1cccc(Cl)c1F
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cccc(Cl)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3-chloro-2-fluorophenol: 1H-NMR (CDCl3) δ 8.55 (1H, d, J=2.7 Hz), 8.11 (1H, d, J=2.7 Hz), 8.03–8.00 (2H, m), 7.96–7.93 (1H, m), 7.45–7.35 (3H, m), 7.27–7.15 (2H, m), 5.43–5.35 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 463 (M+H)+, 461 (M−H)−.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:44]1[C:45]([OH:53])=[CH:46][C:47]3[O:51][CH2:50][CH2:49][C:48]=3[CH:52]=1)([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)OCC3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [4-bromo-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (99%): MS (ES+) m/z 463.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[CH2:43][CH2:42][CH2:41][NH:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:40]3[CH2:41][CH2:42][CH2:43][CH:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CC1CCCN1
Product: CC1CCCN1c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methylpyrrolidine according to conditions described in general procedure C. Mp: 93-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.64 (bs, 2 H), 1.11 (bs, 1 H), 1.58-1.61 (m, 6 H), 1.73-1.84 (m, 4 H), 3.27-3.36 (m, 7 H), 6.24 (s, 1 H), 6.95 (d, J=12.8 Hz, 1 H), 7.14 (d, J=8.4 Hz, 1 H), 7.39 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.53-7.63 (m, 3 H), 7.81 (d, J=6.5 Hz, 1 H), 7.96 (d, J =7.7 Hz, 1 H), 8.22 (d, J=5.5 Hz, 1 H), 10.42 (s, 1 H).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:14]S(C(C)(C)C)=O)[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].Cl.O1CCOCC1>CO>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CCC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of methyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)butanoate (330 mg; 0.88 mmol) in MeOH (4 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.44 ml; 1.77 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate. LC-MS (conditions A): tR=0.56 min.; [M+H]+: 270.06 g/mol.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12]CC)(=[O:11])[C:6]([O:8]CC)=O.[OH:15][CH2:16][PH:17]([CH2:19][CH2:20]C(OCC)=O)=[O:18]>C1(C)C=CC=CC=1>[OH:15][CH2:16][PH:17]([CH2:19][CH2:20][C:6](=[O:8])[C:5]([OH:12])=[O:11])=[O:18]
Reactant: CCOC(=O)CC[PH](=O)CO
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)C(=O)CC[PH](=O)CO
Reaction time: 16 h
Yield: 38.7 %

Procedure:
A suspension of sodium ethoxide in toluene (50 ml) was prepared as in (a) above and to this was added diethyl oxalate (10.9 g) and a solution of ethyl 3-(hydroxymethylphosphinyl)propanoate (13.5 g) in toluene (75 ml). The mixture was stirred for 16 hours then extracted with water (4×60 ml). The extract was acidified with conc. hydrochloric acid (200 ml) and the acid solution refluxed for 2.5 hours. The crude product (8.8 g) was isolated as in part (a) and triturated with acetone to give the desired product (5.2 g).