Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20](O)=O)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[CH2:1]([C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[NH:32][C:31]4[C:26]([N:25]=3)=[N:27][CH:28]=[CH:29][CH:30]=4)[CH2:16][CH2:15]2)=[C:10]([CH3:23])[C:9]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Cc2ccccc2)nnc(N2CCC(C(=O)O)CC2)c1C
Reactant: Nc1cccnc1N
Solvent: ClCCl
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(c3nc4ncccc4[nH]3)CC2)c1C
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidine-4-carboxylic acid (compound 26, 50 mg, 0.15 mmol) and 2,3-diaminopyridine (33 mg, 0.30 mmol) in CH2Cl2 (0.5 mL) is added polyphosphoric acid (1 mL). The mixture is concentrated to remove CH2Cl2. After being stirred at 150° C. for 1.5 h, the mixture is cooled to 25° C., diluted with water (10 mL), and basified by 10% aqueous solution of sodium hydroxide to pH˜8. The aqueous solution is extracted with CH2Cl2 (5×15 mL). The combined organic layers are concentrated and purified by HPLC (CH3CN/H2O: 22% 45% with 0.1% TFA) to give 2-[1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-piperidin-4-yl]-1H-imidazo[4,5-b]pyridine (33.8 mg, 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:14])[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:14][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(O)c(OC)c(F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(OC)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.4 %

Procedure:
To a solution of methyl 3-fluoro-5-hydroxy-4-(methyloxy)benzoate (3.63 g, 18.1 mmol.) in DMF (25 mL) was added cesium carbonate (8.9 g, 27.2 mmol.) followed by benzyl bromide (2.8 mL, 23.6 mmol.) and the mixture was stirred at room temperature over 12 hours. The mixture was then partitioned with ethyl ether and water and the organic phase washed with water (3×) then saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Filtration and concentration followed by purification of the residue by silica gel flash chromatography using 50% hexanes in chloroform as eluent afforded methyl 3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]benzoate (3.54 g, 67% yield) as a colorless solid after concentration of the pure fractions and drying in vacuo.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[CH:25][C:23](N)=[C:22]([F:27])[CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[C:22]([F:27])[CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(Cl)cc1F
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4F)c3c2s1
Yield: 56 %

Procedure:
Prepared from VII and 4-chloro-2-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 56%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2231, 1638, 1614, 1583, 1476, 1413, 1380, 1356, 1309, 1273, 1200, 1170, 1120, 982, 901, 838, 820; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (d, 1H, J=9.0 Hz), 8.24 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.34 (t, 1H, J=8.4 Hz), 7.26 (d, 1H, J=9.0 Hz); HRMS calcd for C16H8N5SClF (M+H+): 356.0173, found 356.0160.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([C:19]1C=C([N+]([O-])=O)C=C2[C:28]=1N=CC=C2)(O)=O>>[C:6]([C:5]1[CH:11]=[C:12]2[C:2](=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)[N:1]=[CH:28][CH:19]=[CH:16]2)([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2cccnc12
Product: O=C(O)c1cc([N+](=O)[O-])c2ncccc2c1
Yield: 61 %

Procedure:
6-Carboxy-8-nitroquinoline was prepared from ethyl 4-amino-3-nitrobenzoate using the method described for 8-carboxy-6-nitroquinoline in example 1. (Yield: 61%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:14]1[N:25]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][CH2:23][N:22]([CH2:30][C:31]([OH:33])=[O:32])[CH2:21][CH2:20][N:19]([CH:34]([C:44]([OH:46])=[O:45])[CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:18][CH2:17][N:16]([CH2:47][C:48]([OH:50])=[O:49])[CH2:15]1>FC(F)(F)C(O)=O>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH2:14]1[N:25]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][CH2:23][N:22]([CH2:30][C:31]([OH:33])=[O:32])[CH2:21][CH2:20][N:19]([CH:34]([C:44]([OH:46])=[O:45])[CH2:35][CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[CH:41][CH:42]=2)[CH2:18][CH2:17][N:16]([CH2:47][C:48]([OH:50])=[O:49])[CH2:15]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Nc1ccc(CCC(C(=O)O)N2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)O

Procedure:
Crude BOC-Ala-PA-DOTA from above was dissolved in trifluoroacetic acid (3.5 mL) and immediately evaporated to dryness under a stream of dry nitrogen. The solid residue was triturated twice with ether (15 mL) and twice with THF (15 mL) to give L-Ala-PA-DOTA (0.066 g: MF (FAB) m/e 617 (positive ion M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:9][N:8]([CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1n[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nn(COC(=O)C(C)(C)C)c2ncc(Br)cc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (4.8 g, 15.8 mmol) in DMF (60 ml) at −40° C. under nitrogen, sodium hydride (1.1 g, 47.3 mmol) was added. The mixture was stirred at −40° C. for 1 hour. Then 2,2-dimethyl-propionic acid chloromethyl ester (6.9 ml, 47.3 mmol; chloromethyl pivalate) in DMF (20 ml) was added dropwise and the resulting mixture was allowed to stir at 40° C. for another 2 hours. The reaction was quenched with saturated aqueous NH4Cl (40 ml) and worked up with ethyl acetate, brine, dried with Na2SO4 and evaporated. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2,2-dimethyl-propionic acid 5-bromo-3-(2-methoxy-phenyl)-pyrazolo[3,4,b]pyridine-1-ylmethyl ester (4.1 g, 62% yield). 1H NMR (500 MHz, DMSO-d6) δ 1.11 (s, 9H), 3.85 (s, 3H), 6.46 (s, 2H), 7.09 (m, 1H), 7.24 (d, 1H), 7.51 (m, 1H), 7.60 (d, 1H), 8.43 (s, 1H), 8.74 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)[CH3:9])=[CH:20][CH:21]=1)#[N:2]
Reactant: COC(=O)c1ccc(C(C)Oc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccc(C#N)cc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A mixture of methyl 4-(1-(4-cyanophenoxy)ethyl)benzoate (370 mg, 1.3 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (45 mL), methanol (15 mL) and water (15 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (55 mL×3). The combined organic phase was dried by sodium sulfate, then filtered. The filtrate was evaporated in vacuo to give 4-(1-(4-cyanophenoxy)ethyl)benzoic acid (310 mg, 74%) as a white solid. LRMS (M+H+) m/z: cald 267.09. found 267.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][NH:7][C:6]=2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO>CN(C=O)C>[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:27])[N:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[CH2:16][CH2:15]3)[C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2[nH]nc3cc(F)ccc23)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 37.8 %

Procedure:
To a solution consisting of 2-[4-(6-fluoro-2H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to 80 C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55 C.) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186°-188° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]([CH3:17])[C:6]1[S:10][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][CH:7]=1)=[O:4].[Cl:20]N1C(=O)CCC1=O>C(#N)C>[Cl:20][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[N:5]([CH3:17])[C:3](=[O:4])[C:2]([F:18])([F:1])[F:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CN(C(=O)C(F)(F)F)c1cnc(-c2cccnc2)s1
Solvent: CC#N
Product: CN(C(=O)C(F)(F)F)c1sc(-c2cccnc2)nc1Cl
Temperature: 63 °C

Procedure:
A suspension of 2,2,2-trifluoro-N-methyl-N-(2-pyridin-3-yl-thiazol-5-yl)-acetamide (1.0 g, 3.5 mmol) and N-chlorosuccinimide (0.557 g, 4.2 mmol) in acetonitrile (30 mL) was heated to 63° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature and it was treated with additional N-chlorosuccinimide (0.557 g, 4.2 mmol) and heated to 35° C. under nitrogen for 2 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was redissolved in dichloromethane (80 mL) and washed with water (70 mL). The aqueous layer was re-extracted with methylene chloride (100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure and purified using reverse phase chromatography. The product eluted with a gradient of acetonitrile in water. The desired product was isolated as a thick brown gum (0.337 g, 30%): 1H NMR (400 MHz, CDCl3) δ 9.12 (br, 1H), 8.75 (br, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.28 (br, 1H), 3.40 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −69.3; ESIMS m/z 324.3 (M+2); IR (thin film) 1772 cm−1.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[Cl:16].[OH-].[Na+].Cl>CO.O>[Cl:16][C:5]1[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(N2CCOCC2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-benzoic acid methyl ester (3.08 g, 12.0 mmol) and 6N NaOH (2.5 mL, 15 mmol) in methanol (50 mL) and water (7.5 mL) was stirred 24 h at room temperature, then acidified with 2N HCl. The precipitate was filtered off, washed with water and dried to provide 2-chloro-4-morpholin-4-yl-benzoic acid (2.56 g, 88% yield) as a white solid. This intermediate (10.6 mmol) was suspended in tert-butanol (20 mL), treated with diphenylphosphoryl azide (2.30 mL, 10.6 mmol), then with triethylamine (1.45 mL, 10.6 mmol), was stirred at reflux for 20 h and evaporated. Purification by flash chromatography (SiO2) eluted with 2:8 ethyl acetate:hexanes provided (2-chloro-4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (2.84 g) as a mixture (˜1:1) with 2-chloro-4-morpholin-4-yl-benzoic acid tert-butyl ester. This mixture was carried on without further purification. 1H-NMR (CDCl3, 500 MHz) 8.0 (br, 1H), 7.80 (d, 1H), 7.4 (d, 1H), 6.90 (d, 1H), 6.87 (d, 1H), 6.84 (dd, 1H), 6.75 (dd, 1H), 3.87 (m, 8H), 3.26 (m, 4H), 3.11 (m, 4H), 1.61 (s, 9H), 1.55 (s, 9H) ppm; MS (FIA) 313.1 (M+H); HPLC (Method A) 3.70 min.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:28])[C:8]([C@H:13]([OH:27])[C:14]([O:16][C@@H:17]3[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]3[CH:24]([CH3:26])[CH3:25])=[O:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O.O>C(OC(C)=O)(C)(C)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:28])[C:8]([C@H:13]([O:27][C:5]([CH3:10])([CH3:6])[CH3:4])[C:14]([O:16][C@@H:17]3[CH2:22][C@H:21]([CH3:23])[CH2:20][CH2:19][C@H:18]3[CH:24]([CH3:25])[CH3:26])=[O:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1
Reactant: Cc1cc2ccc(Br)cc2c(O)c1[C@H](O)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)OC(C)(C)C
Product: Cc1cc2ccc(Br)cc2c(O)c1[C@H](OC(C)(C)C)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reaction time: 3 h

Procedure:
To a solution of (S)-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 2-(7-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate in t-BuOAc (150 mL) was added 70% perchloric acid (HClO4) (3.0 mL). After 3 h, water was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes). Upon sitting, crystals formed in the resulting oil that were the desired diastereomer. 1H-NMR: 400 MHz, (CDCl3) δ: 9.11 (s, 1H), 8.39 (s, 1H), 7.48 (m, 2H), 7.10 (s, 1H), 5.46 (s, 1H), 4.66 (m, 2H), 2.53 (s, 3H), 1.71 (m, 2H), 1.62 (m, 2H), 1.36 (m, 2H), 1.32 (s, 9H), 0.80 (m, 7H), 0.60 (d, J=6 Hz, 3H).
Reaction SMILES: [OH-].[Na+:2].[OH-].[NH4+:4].[C:5]([OH:16])(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1>>[C:5]([O-:16])(=[O:15])[C:6]1[CH:14]=[CH:13][C:9]([C:10]([O-:12])=[O:11])=[CH:8][CH:7]=1.[NH4+:4].[Na+:2]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
FIG. 1 is a diagram of the invented process using sodium hydroxide and ammonium hydroxide. Terephthalic acid, sodium hydroxide and ammonium hydroxide are metered into reservoir 1 by lines 2, 3 and 4 in ratios of one mole per mole at the beginning of the electrochemical reduction process to form sodium ammonium terephthalate. Added ammonium hydroxide is used as a buffer to raise the pH from approximately 7 to within the range of from about 8.0 to about 11.0. The sodium ammonium salt solution is thereupon pumped by suitable means by line 5 to electrolysis cell 6 wherein the salt of terephthalic acid is reduced to sodium p-hydroxymethylbenzoate (Na p-HMB). The Na p-HMB is thereupon pumped by line 7 back to the reservoir 1 which contains Na p-HMB, NH4OH, and monosodium terephthalate. After optimum levels of Na p-HMB have been reached in the reservoir 1, a portion of the electrolysis cell output of line 7 is pumped by line 8 to reactor 9 to which make-up terephthalic acid and make-up sodium hydroxide are added by lines 10 and 11. Make-up terephthalic acid and sodium hydroxide are required because of the reduction of the sodium ammonium terephthalate to Na p-HMB and to salt out the Na p-HMB. Recycle ammonium salt from reactor 9 is pumped by line 25 to line 18 and thence to reservoir 1. The disodium terephthalate in reactor 9 is pumped with the solution removed from reservoir 1 by line 12 to chill unit 13 wherein the Na p-HMB is salted out by the presence of the disodium terephthalate. The resulting slurry in chill unit 13 is pumped by line 14 to filter 15 wherein solids comprising Na p-HMB are filtered and forwarded by line 16 to be recrystallized in crystallizer 17. Mother liquor from filter 15 is recycled to reservoir 1 by line 18. Mother liquor after dewatering from crystallizer 17 is recycled to reservoir 1 by line 19, which joins line 18. Recycle slurry from filter 15 is returned to chill unit 13 by line 22 if recycle is necessary to obtain sufficient cooling. Make-up terephthalic acid and ammonium hydroxide are added to line 18 by lines 20 and 21 to restore the sodium:ammonium:terephthalate ratio and are reacted in reservoir 1. Sodium p-hydroxymethylbenzoate is removed from crystallizer 17 by line 25 to reactor 23 where it is acidified to obtain p-hydroxymethylbenzoic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[N:19][C:18]=2[C:34]([O:36]CC)=[O:35])[CH:13]=[CH:12][CH:11]=1)[N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.CO.[OH-].[K+].Cl>C(O)(C)(C)C>[OH:1][CH2:2][CH:3]([C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:27]=3)=[N:19][C:18]=2[C:34]([OH:36])=[O:35])[CH:13]=[CH:12][CH:11]=1)[N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: CO
Product: O=C(O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1Nc1cccc(C(CO)N2CCOCC2)n1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
Ethyl 5-{[6-(2-hydroxy-1-morpholin-4-ylethyl)pyridin-2-yl]amino}-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxylate (68 mg, 0.126 mmol) was taken up in tert-butanol (1.3 mL) and methanol (1.3 mL) and aqueous 1.0 M potassium hydroxide (0.63 mL, 0.63 mmol) was added. The resulting slurry was stirred at 60° C. for 4.5 hrs (the slurry became a homogenous yellow solution soon after reaching 60° C.). The reaction was cooled to room temperature and neutralized with 0.63 mL 1M aqueous hydrochloric acid. A yellow precipitate then formed. The resulting slurry was concentrated under reduced pressure, suspended in methanol, and concentrated again to afford the title compound as a yellow solid. LRMS (APCI) calcd for C24H29N6O5S [M+H]+, 513.2; found 513.0.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[CH3:8][C:9]1[C:10]([CH2:20][C:21]#[N:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1.CO>C1COCC1>[CH3:8][C:9]1[C:10]([CH2:20][CH2:21][NH2:22])=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1
Reactant: Cc1cn(-c2ccccc2)nc1CC#N
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2ccccc2)nc1CCN
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
To lithium borohydride (2M solution in THF, 629 μL, 1.26 mmol) was added dropwise trimethylchlorosilane (273 mg, 321 μL, 2.51 mmol) over a period of 5 min at 0-5° C. At that temperature a solution of 2-(4-methyl-1-phenyl-1H-pyrazol-3-yl)acetonitrile (62 mg, 314 μmol) in THF (0.5 mL) was added dropwise. The mixture was stirred at 70° C. for 1.5 h. After cooling down to 0-5° C., MeOH (0.5 mL) was added dropwise. After 10 min the ice bath was removed and the mixture was allowed to warm up to RT. The reaction mixture was poured into NaOH (1 M, 10 mL) and extracted with dichloromethane (3×25 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give the product as light yellow semisolid (46 mg, 206 μmol, 65.4%) which was used without further purification for the next step.
Reaction SMILES: Cl.C([O:4][C:5](=O)[CH2:6][NH:7][CH3:8])C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[S:18])[CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:8][N:7]1[CH2:6][C:5](=[O:4])[N:16]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[C:17]1=[S:18]
Reactant: S=C=Nc1cccnc1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(c2cccnc2)C1=S
Yield: 39.6 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), pyridin-3-yl-isothiocyanate (6.8 g), triethyl amine (10.1 g) and chloroform (200 mL) was heated at reflux for 3.5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (300 mL) and washed with water (2×200 mL). The organic phase was dried over anhydrous magnesium sulfate. The solvent was evaporated. Crystallization from ethyl acetate afforded the title compound (4.1 g) as an off-white solid, m.p. 149°-151°C. Anal. Calcd. for C9H9N3O S: C, 52.16; H, 4.38; N, 20.28. Found: C, 52.16; H, 4.05; N, 20.06. Mass spectrum (EI, M.+) m/z 207.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[C:4]([C:9]2[N:18]=[C:17]3[C:12]([C:13]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=4)=[CH:14][C:15]([C:19]#[N:20])=[N:16]3)=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:34]S(O)(=O)=O>>[F:33][C:2]([F:1])([F:32])[C:3]1[C:4]([C:9]2[N:18]=[C:17]3[C:12]([C:13]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][N:23]=4)=[CH:14][C:15]([C:19]([NH2:20])=[O:34])=[N:16]3)=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Product: NC(=O)c1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 7-[3-(trifluoromethyl)pyridin-2-yl]-4-{[5-(trifluoromethyl)pyridin-2-yl]amino}-1,8-naphthyridine-2-carbonitrile (25 mg, 0.054 mmol) in concentrated H2SO4 (2 mL) and stir the mixture overnight at ambient temperature. Pour the mixture onto ice and adjust the pH to about 7-8. Filter off the resulting precipitate to yield the title compound as an off-white solid. MS 479.02 (M+1). 1H NMR δ (CD3OD) 9.32 (1H, s), 9.10 (1H, d), 8.97 (1H, d), 8.71 (1H, s), 8.41 (1H, d), 8.05 (1H, d), 7.95 (1H, d), 7.82 (1H, m), 8.90 (1H,s), 7.44.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][NH:19][CH2:20][CH2:21][CH3:22]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][N:19]([CH3:18])[CH2:20][CH2:21][CH3:22])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CCCNC
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCCN(C)CC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (8.5 mg, 0.026 mmol), N-methylpropan-1-amine (0.50 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.3), 95 (5), 87 (6), 86 (bp), 75 (5), 58 (15).