Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH:11]([C:18]1[N:19]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:20]2[C:25]([C:26](=[O:28])[CH:27]=1)=[C:24]([CH3:29])[CH:23]=[C:22]([Cl:30])[N:21]=2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Cl:30][C:22]1[N:21]=[C:20]2[C:25]([C:26](=[O:28])[CH:27]=[C:18]([N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[N:19]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:24]([CH3:29])[CH:23]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1cc(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Solvent: ClCCl
Product: Cc1cc(Cl)nc2c1c(=O)cc(N(C(=O)Nc1ccc(F)cc1)c1ccccc1)n2-c1ccccc1
Reaction time: 16 h
Yield: 1.6 %

Procedure:
4-Fluorophenyl isocyanate (45.0 mg, 0.33 mmol) was added to a stirred solution of 2-anilino-7-chloro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (100 mg, 0.276 mmol) in CH2Cl2 (3 mL). After 16 h, an additional equivalent of 4-fluorophenyl isocyanate (45.0 mg) was added, and the reaction stirred for an additional 16 h. The reaction was concentrated in vacuo and the residue was dissolved in EtOAc. The solution was washed with 1 N HCl, dried over MgSO4, and concentrated in vacuo. Purification of the residue using reverse phase prep-HPLC afforded N-(7-chloro-5-methyl-4-oxo-1-phenyl-1,4-dihydro-1,8-naphthyridin-2-yl)-N′-(4-fluorophenyl)-N-phenylurea (2.2 mg, 1.6%): LCMS RT: 3.47 min, MH+: 499.1, Rf=0.52 (1:1 EtOAc:Hex).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[OH-].[Na+].[C:7]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C>O>[CH3:1][C:2](=[C:8]1[CH2:9][CH2:10][CH2:11][C:7]1=[O:12])[CH3:4]
Reactant: O=C1CCCC1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)=C1CCCC1=O

Procedure:
A mixture of 190 ml of acetone and 36.0 g of sodium hydroxide in 600 ml of water was treated with 60.0 g of cyclopentanone under stirring. After stirring for about 12 hours at about room temperature, the mixture was neutralized with 36% acetic acid and extracted with three 60 ml portions of ether. The combined extracts were dried over anhydrous magnesium sulfate and evaporated to give a residue. The residue was distilled to obtain 62.6 g of 2-(1-methylethylidene) cyclopentanone as a colorless liquid. The boiling point of this intermediate compound was determined to be 85°-88° C. at a pressure of 10 mm Hg. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(1-methylethylidene) cyclopentanone hydrochloride. The melting point of the product was determined to be 173°-175° C.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[N:30]=[CH:29][CH:28]=[N:27]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH:32]1([C:2]2[C:3]([NH:12][C@H:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:26]3[N:30]=[CH:29][CH:28]=[N:27]3)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH2:34][CH2:33]1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl)c1ccccc1-n1nccn1
Reactant: OB(O)C1CC1
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: C1COCCO1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ccccc1-n1nccn1

Procedure:
A mixture of N-[(1S,2S)-2-{[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 29; 170 mg, 0.38 mmol), cyclopropylboronic acid (CAS number 411235-57-9; 97 mg, 1.13 mmol), potassium carbonate (aq. 2 M, 752 μl, 1.51 mmol) and tetrakis(triphenylphosphine)palladium (44 mg, 0.038 mmol) in 1,4-dioxane (1.3 ml) was sealed, purged and evacuated with nitrogen and then subjected to microwave irradiation 120° C. for 1 hour. The reaction was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. This was then purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH:15]3[CH2:17][C:11]([C:18]([OH:20])=O)([CH2:12][CH:13]1[CH2:14]3)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:23](C(C)C)C(C)C.N.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]12[CH2:16][CH:15]3[CH2:17][C:11]([C:18](=[O:20])[NH2:23])([CH2:12][CH:13]1[CH2:14]3)[CH2:10]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(C(=O)O)(C3)C2
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC12CC3CC1CC(C(N)=O)(C3)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3a-tert-Butoxycarbonylaminohexahydro-2,5-methanopentalene-2-carboxylic acid was dissolved in DMF (200 ml), and DIPEA (10.6 g) and ammonia (6.1 ml, 7M in MeOH) were added. Subsequently, HATU (14.8 g) was added and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated by rotary evaporation down to volume 50 ml, poured into 400 ml of dilute NaHCO3 solution (300 ml of H2O+100 ml of saturated NaHCO3 solution) and extracted 3 times with 100 ml of EtOAc. Then dried over MgSO4, filtered and concentrated by rotary evaporation.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Br:18])[CH:8]=[CH:9][C:10]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:5]1)(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Br:18])[CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[C:10]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Br)c2c1CCN(C(C)=O)C2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CCN(C(C)=O)C2
Temperature: 25 °C

Procedure:
The product from Example 21 (31 g) was dissolved in trifluoroacetic acid (450 mL). The solution was treated dropwise with 33 mL of fuming 90% nitric acid and stirred at room temperature. The reaction mixture was concentrated, the residue was dissolved in chloroform and then washed well with sodium bicarbonate solution. A solid formed, and was dissolved in 3 L chloroform and dried over magnesium sulfate. After evaporation, the residue was crystallized from ethyl acetate to give a white solid (19.32 g), and the filtrate concentrated to give an additional 16.3 g.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:26][CH2:25][C:24]([O:28][CH3:29])=[O:27])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (5.00 g, 0.021 mole) and triethylamine (0.5 ml) in methanol (50 ml) was added methyl acrylate (5.40 g, 0.063 mole). The mixture was stirred under argon at room temperature for about 20 hours. Volatiles were removed in vacuo to give an oil. Chromatography on silica gel and recrystallization from hexane gave the title compound, m.p. 63.5°-65.5°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH2:1]([O:3][C:4](=[O:25])[C:5]([S:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)[N:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(Br)cc2)cs1
Reactant: OB(O)Oc1ccc(F)cc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Sc1nc(CCOCc2ccc(-c3ccc(F)cc3)cc2)cs1
Yield: 43 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(4-bromobenzyl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid ethyl ester (0.9 g) synthesized in Example 155-2 and 4-fluorophenylboric acid (425 mg) were dissolved in dioxane (10 mL) and aqueous sodium carbonate solution (2 mol/L, 5 mL), tetrakis(triphenylphosphine)palladium (117 mg) was added, and the mixture was refluxed for 4 hr. The reaction mixture was cooled, water was added thereto, and the mixture was 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, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=5:1) to give the title compound (400 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12]C1C=CC=CC=1C)=[O:11].C[C:25]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([O:37][CH2:38][CH2:39][NH2:40])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].Cl>CN(C=O)C>[N+:34]([C:33]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[O:37][CH2:38][CH2:39][NH:40][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([N:9]([C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:20])[C:10]([NH2:12])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:27]([OH:29])=[O:28])([O-:36])=[O:35]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: Cc1c(C(=O)O)ccc(OCCN)c1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)NCCOc2ccc(C(=O)O)cc2[N+](=O)[O-])ccc1N(C(N)=O)c1ccccc1C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
To a stirred solution of pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.86 g, 3.87 mmol) and methyl 3-nitro-4-(2-aminoethoxy)benzoic acid (0.93 g, 3.87 mmol) in DMF (27 mL) was added Et3 N (0.90 mL, 6.46 mmol), and the resulting mixture was stirred overnight. The mixture was poured into 0.5 N HCl and the resulting solid was collected. The crude solid was dissolved in THF-0.25 N NaOH (1/1, 20 mL) and the resulting mixture was heated under reflux overnight. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated. The crude solid was recrystallized from CHCl3-EtOH to give 60 mg (3% for 2 steps) 3-nitro-4-[2-[3-methoxy-4-[N-(2-methylphenyl)ureido]phenylacetyl]aminoethoxy]benzoic acid 257 as a yellow crystalline solid. mp 112–115° C.; 1H-NMR (DMSO-d6) d 2.24 (s, 3 H), 3.37–3.66 (m, 7 H), 3.84 (s, 3 H), 4.27–4.30 (m, 1 H), 6.74–8.56 (series of m, total 12 H); MS (FAB) m/z 523 (M++1); Anal. Calcd for C26H26N4O8.3/2H2O: C, 56.83; H, 5.32; N, 10.20. Found: C, 56.66; H, 4.90; N, 9.33.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[C:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2].[NH2:20][C:21]1[NH:25][N:24]=[N:23][N:22]=1>C(O)C>[CH2:12]([O:11][C:9]([C:8]1[CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:22]2[N:23]=[N:24][N:25]=[C:21]2[NH:20][C:14]=1[CH3:15])=[O:10])[CH3:13]
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: Nc1nnn[nH]1
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2nnnn2C1c1cccc([N+](=O)[O-])c1
Yield: 61.3 %

Procedure:
To 50 ml of ethanol are added 2.6 g of ethyl 3-nitro-α-acetylcinnamate and 0.9 g of 5-aminotetrazole, and then heated under reflux for 16 hours. On cooling, 2 g of 6-ethoxycarbonyl-5-methyl-7-(3-nitrophenyl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine, melting at 210°-212° C., is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[NH:3][C:4]([C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[O:26])=[CH:18][C:17]=2[F:37])[CH:7]=1)=[O:5].N[C:40]1C=CC(OC2C=CN=C3C=C(C(N(C)N(C)C)=O)SC=23)=C(F)C=1>>[F:37][C:17]1[CH:18]=[C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[O:26])[CH:20]=[CH:21][C:16]=1[O:15][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:7]=[C:6]([C:4]([N:3]([CH3:40])[N:2]([CH3:1])[CH3:38])=[O:5])[S:14][C:13]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)NN(C)C)sc23)c(F)c1
Reactant: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N(C)N(C)C)sc23)c(F)c1
Yield: 43 %

Procedure:
Following the procedure described above for compound 236 (step 4, example 95, scheme 63) but replacing amine 239 with 7-(4-amino-2-fluorophenoxy)-N,N′,N′-trimethylthieno[3,2-b]pyridine-2-carbohydrazide (244), title compound 241 was obtained in 43% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.45 (s, 1H), 8.45 (d, J=5.4 Hz, 1H), 7.79 (d, J=13.3 Hz, 1H), 7.67 (s, 1H), 7.62-7.31 (m, 7H), 6.62 (d, J=5.4 Hz, 1H), 3.40 (s, 9H), 3.23 (s, 2H), 3.21 (s, 3H). MS (m/z): (M+1) 536.2 (100%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][NH:14]1.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:17]=3[CH2:16][CH2:15][NH:14][C:13]4=[O:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2ccc(Br)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Br)ccc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 6-bromo-1,3-dihydro-indol-2-one (42.4 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[BH4-].[Na+]>CO>[C:1]([NH:9][NH:10][CH:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(NNC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
272 g (2 mol) of benzoic acid hydrazide are added to 1500 ml of methanol with stirring. Over 1 hour, 226 g (2 mol) of 1-methyl-4-piperidinone are then added dropwise at a temperature of 30° C. Slight cooling is necessary. The reaction mixture is stirred for half an hour at 30° C. and then for a further 1 hour at 60° C. The solution is then cooled to 0° C. and over a period of 2 hours 68 g (1.8 mol) NaBH4 is added using a spatula (strong foaming). Towards the end of the addition the mixture is warmed to room temperature. The solvent is evaporated off using a rotary evaporator and to the residue 900 g ice and 1000 ml dichloromethane are added with stirring. The organic phase is separated using a separating funnel and the aqueous phase is shaken twice with 300 ml dichloromethane in each case. The combined organic fractions are dried over MgSO4, the dichloromethane evaporated off and the residue recrystallized in 1 liter of isopropanol with the addition of 10 g active charcoal. The reaction product is dried in a drying cupboard at 50° C. in vacuo. (M.p. 149°-150° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:9]CCC(OC)=O)=[N:5][CH:6]=[CH:7][N:8]=1)#[N:2].[OH-].[Na+].[H][H]>O1CCCC1>[SH:9][C:4]1[C:3]([C:1]#[N:2])=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: COC(=O)CCSc1nccnc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1nccnc1S
Temperature: 50 °C
Reaction time: 1 h
Yield: 115.2 %

Procedure:
To a solution of methyl 3-(3-cyanopyrazin-2-ylthio)propanoate (1.56 g, 6.96 mmol) in anhydrous tetrahydrofuran at room temperature was added 60% sodium hydroxide suspension (0.34 g, 8.4 mmol). Vigorous hydrogen evolution was observed. After 1 h at room temperature there appeared to be no reaction, the reaction temperature was raised to 50° C. for 6 h, whereupon the starting material was consumed by TLC. The reaction was quenched by the addition ice, followed by 5% aqueous citric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 3-mercaptopyrazine-2-carbonitrile (1.1 g) as an orange solid. MW=137 confirmed by LC-MS, tr=4.79 min (Method Y) MH+=136-138.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[H][H]>C(O)(=O)C.[Pt](=O)=O>[CH2:1]([C@H:5]1[CH2:13][CH2:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-isobutylbenzoic acid (1.0 g, 5.6 mmol) in acetic acid (56 ml) was purged with argon. After addition of platinum(IV) oxide (0.38 g, 1.7 mmol) the reaction flask was filled with hydrogen gas. The reaction mixture was stirred under an atmosphere of hydrogen gas for 72 h at RT. The flask was purged with argon, and the catalyst was removed by filtration over Decalite. The filtrate was concentrated to dryness to give the title compound as a (7:3) cis/trans mixture. MS m/e: 183 ([M−H]−)
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[OH-].[Na+].S([O-])(O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)=O>>[CH2:26]([O:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15]
Reactant: CCN(CC)CCO
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCOCCN(CC)CC
Temperature: 20 °C

Procedure:
140.6 grams (1.2 moles) of diethyl ethanolamine, 48 grams (1.2 moles) of sodium hydroxide and 288.4 grams (1 mole) of lauryl sulfate, Na salt were reacted under a nitrogen atmosphere using the procedure of Example 9. Approx. 20 grams of the diethyl ethanolamine evaporated from the reaction with water during the reaction and was immediately replaced. After a reaction time of 2 hours at 190° C., followed by cooling to 20° C., the reaction mixture was purified using the procedure of Example 2. 168 grams of an oily liquid having an amine number of 151 were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>C(O)C>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:22]=[C:21]2[C:20](=[CH:19][CH:18]=1)[NH:23][C:9]1[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C:8]2=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Yield: 147.7 %

Procedure:
A mixture of 4-oxocyclohexane carboxylic acid ethyl ester (3.75 g, 0.022 mol), 4-trifluoromethoxy phenylhydrazine hydrochloride (5 g, 0.0218 mol) and anhydrous ethanol (68 mL) was refluxed overnight under nitrogen. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic extracts were washed with 1:1 water/brine and dried over anhydrous magnesium sulfate. Removal of the solvent provided a yellow solid that was dried in vacuo (7.15 g). The material from two runs (11.64 g) was chromatographed on silica gel Merck 60 using a 5 to 15% gradient of ethyl acetate in hexane to yield the title compound as a pale tan solid (10.54 g, 92%), m.p. 131-132° C. MS [(+)ES, m/z}: 328.1 [M+H]+. MS [(−)ES, m/z]: 326.1 {M−H]−. HPLC: Chromolith Monolith column, 0.46×10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 280 nm; Rt 2.45 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[N:3]=1.OS(O)(=O)=O.[CH3:16][CH2:17]O>C(Cl)Cl>[CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([O:10][CH2:16][CH3:17])=[O:9])[N:3]=1
Reactant: Cc1ccn(CC(=O)O)n1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)Cn1ccc(C)n1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A suspension of (3-methyl-1H-pyrazol-1-yl)acetic acid (200 mg) and H2SO4 (0.1 mL) in EtOH (2 mL) was stirred at 80° C. for 4 h. After cooling down, the reaction mixture was diluted with DCM and washed with sat. Na2CO3, water and brine. The aq. layers were extracted with DCM, the combined org. layers were dried (MgSO4), filtered off and evaporated in vacuo to afford ethyl 2-(3-methyl-1H-pyrazol-1-yl)acetate (101 mg, colourless liquid). LC-MS (B): tR=0.57 min; [M+H]+: 169.01.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:35])=[CH:9][C:10]([O:33][CH3:34])=[CH:11][C:12]=3[C:13]32[CH2:20][CH2:19][O:18][C:17]([NH:21]C(=O)C2C=CC([N+]([O-])=O)=CC=2)=[N:16]3)=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:35])=[CH:9][C:10]([O:33][CH3:34])=[CH:11][C:12]=3[C:13]32[CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1
Reactant: COc1cc(F)c2c(c1)C1(CCOC(NC(=O)c3ccc([N+](=O)[O-])cc3)=N1)c1cc(Br)ccc1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(F)c2c(c1)C1(CCOC(N)=N1)c1cc(Br)ccc1O2
Temperature: 65 °C
Yield: 89.7 %

Procedure:
A suspension of N-(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2-yl)-4-nitrobenzamide (6.0 g, 11.06 mmol) in methanol (60 mL) was heated to 65° C. NaOH (2 M solution) (48.7 ml, 97 mmol) was added and the resulting mixture was heated to 65° C. for 4 hrs. The reaction mixture was concentrated under reduced pressure, the precipitate was filtered off, washed twice with water and dried to afford 7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-2-amine (3.90 g, 9.92 mmol, 50.9% yield) as white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:15]3[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[O:17][N:16]=3)[CH:11]=[CH:12][C:13]=2[CH3:14])=[N:6][CH:7]=1.[O:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:25]=[C:24]1[C:32](O)=[O:33]>>[CH3:21][C:18]1([CH3:22])[O:17][N:16]=[C:15]([C:10]2[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([C:5]3[N:6]=[CH:7][C:2]([NH:1][C:32]([C:24]4[O:23][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[CH:25]=4)=[O:33])=[N:3][CH:4]=3)[CH:9]=2)[C:19]1=[O:20]
Reactant: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(N)cn1
Reactant: O=C(O)c1cc2ccccc2o1
Product: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(NC(=O)c2cc3ccccc3o2)cn1

Procedure:
The title compound was prepared by following a procedure similar to that described in method B of Examples 97 to 118 by using Intermediate 1b and benzofuran-2-carboxylic acid. 1HNMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 9.04 (s, 1H, D2O exchangeable), 8.50 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.09 (dd, J=8.0, 2.0 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.70 (s, 1H), 7.59 (dd, J=8.5, 1.0 Hz, 1H), 7.51 (dt, J=7.5, 1.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.36 (dt, J=8.0, 1.0 Hz, 1H), 2.48 (s, 3H), 1.47 (s, 6H); ESI-MS (m/z) 441 (MH)+.