Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](=[O:10])[NH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19]>CN(C=O)C>[CH2:17]([N:3]1[C:4](=[O:10])[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2]1)[CH2:18][CH3:19]
Reactant: O=c1[nH]cnc2[nH]ccc12
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cnc2[nH]ccc2c1=O
Temperature: 55 °C
Reaction time: 20 h

Procedure:
Under argon gas, 7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.0 g) was dissolved in DMF (35 ml) with warming. Then, anhydrous potassium carbonate (1.02 g) and propyl iodide (1.08 ml) were added and the mixture was stirred at 55° C. for 20 hours. The insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The residue was purified by flash column chromatography (silica gel; hexane: ethyl acetate=4:1-1:1) to provide the title compound (521 mg). 1H-NMR (CDCl3) 8: 0.96(3H,t,J=7.4Hz), 1.73-1.92(2H,m), 4.01(2H,t,J=7.4Hz), 6.71(1H,dd,J=2.2&3.4Hz), 7.01(1H,dd,J=2.2&3.4Hz), 7.94(1H,s).
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:16](O)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].CS(O)(=O)=O>>[C:16]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:38])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCCOc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCCOc1ccccc1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 925.05 g (2.08 moles) of the Alkoxylate from example 27 and 674.95 g (1.98 moles) of Behenic Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.O>O1CCCC1>[C:15]([O:14][C:12]([NH:7][C@H:6]([CH2:10][CH2:9][C:8]([C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1)=[O:11])[C:4]([O:3][CH2:2][CH3:1])=[O:5])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (CAS No. 128811-48-3; 4.0 g) in tetrahydrofuran (100 mL), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether; 17.1 mL) was added dropwise at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.6 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[Br-].[CH3:15][C:16](=O)[CH2:17]C>>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])[CH:16]=[CH2:15]
Reactant: CON(C)C(=O)c1cccc(O)c1
Reactant: CCC(C)=O
Agent: [Br-]
Product: C=CCOc1cccc(C(=O)N(C)OC)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 10.8 g (59.6 mmol) B5 and 5.42 ml (71.5 mmol) allylic bromide in 300 ml 2-butanone 41.1 g (298 mmol) potassium carbonate were added. After stirring at 60° C. for 15 hours the solvent was distilled off and the residue partitionated between ethyl acetate and water. The organic layer was dried over sodium sulfate and the solvent removed in vacuo. Yield: 12.1 g (92%) B10 as a yellowish oil which was used without further purification.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH3:1][C:2]1([CH3:9])[CH2:3][O:7][CH:6]1[C:5]1[CH:8]=[CH:9][C:2]([CH:1]2[C:5]([CH3:8])([CH3:6])[CH2:4][O:10]2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)COC1c1ccc(C2OCC2(C)C)cc1
Yield: 80 %

Procedure:
Isobutyl aldehyde of 4.2 equivalent amount and a 1.0 equivalent amount of terephthalaldehyde were dissolved in methanol, and a methanol solution of a 2.1 equivalent amount of potassium hydroxide was dropwise added thereto at room temperature. The resulting solution was reacted at 60° C. for 6 hours, and concentrated under reduced pressure. The concentrate was dissolved in water ten times the concentrate while heating and allowed to cool to precipitate crystals. The precipitated crystals were filtered off, washed with water, and dried over a drying agent for 2 days under reduced pressure to obtain white crystals, 1,4-bis(3,3-dimethyloxetan-2-yl)-benzene. The yield was 80 to 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[OH:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1ccccc1O
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1ccccc1O

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-phenyl)-6-(2, 2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example E) and 2-hydroxy-benzoic acid (CAN 69-72-7) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 421.5080 (M−H)−.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)=[O:6]>O.CO>[C:12]1([C:9]2[O:8][C:7]([C:5]([OH:6])=[O:4])=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
A solution of sodium hydroxide (200 mg) in water (5 ml) was added to a stirred solution of 5-phenyl-furan-2-carboxylic acid methyl ester (7) (384 mg, 1.90 mmoles) in methanol (20 ml) and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue was diluted with water (10 ml) and acidified to pH=2 with 1 M aqueous hydrochloric acid. The precipitate was collected, washed with water and the residue was triturated with cyclohexane to afford (8) (350 mg) as a white solid. LC/MS System A; Rt=3.89 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[N:6][CH:7]=1.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:24][CH2:25]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNCC1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCCC2)CC1
Yield: 65.2 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide (100 mg, 0.205 mmol), cyclohexanone (0.106 mL, 1.02 mmol), and sodium cyanoborohydride (51 mg, 0.82 mmol) yielded, after treatment with HCl, 33 mg (33%) of the title compound as a hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[CH3:9])=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: CNc1ccc(Cl)cn1
Product: COC(=O)C(=O)N(C)c1ccc(Cl)cn1

Procedure:
The method described in Referential Example 242 was performed by use of 5-chloro-N-methyl-2-pyridinamine and methyl chlorooxoacetate, whereby the title compound was obtained. 1H-NMR(CDCl3)δ: 3.43(3H, s), 3.81(3H, s), 7.08(1H, br.s), 7.68-7.78(1H, m), 8.27(1H, br.s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[Cl:36][C:37]1[N:42]=[CH:41][C:40]([NH:43][CH:44]([CH3:46])[CH3:45])=[CH:39][CH:38]=1.P(Cl)(Cl)Cl>C1C=CC=CC=1>[Cl:36][C:37]1[N:42]=[CH:41][C:40]([N:43]([CH:44]([CH3:46])[CH3:45])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:39][CH:38]=1
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: CC(C)Nc1ccc(Cl)nc1
Solvent: c1ccccc1
Solvent: ClP(Cl)Cl
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccc(Cl)nc1
Temperature: 25 °C
Yield: 13.5 %

Procedure:
To a solution of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (30 mg, 0.06 mmol) and (6-chloro-pyridin-3-yl)-isopropyl-amine (Preparation 2(A)) (10.1 mg, 0.06 mmol) in benzene (2 mL) was added PCl3 (2.0 M in CH2Cl2, 0.1 mL, 0.198 mmol) and the reaction was heated at reflux for 24 hours. The reaction was cooled to room temperature and was diluted with CH2CO2. The organic solution was washed consecutively with aqueous NaHCO3 (1×), water (1×), 1N HCl (1×), and water (1×). The organic solution was dried (MgSO4) and the volatiles were concentrated in vacuo. The residue was purified by medium pressure chromatography eluting with 10% EtOH in CH2Cl2 to yield 5 mg of N-(6-chloro-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CDCl3) δ 8.26 (s, 1H), 8.17 (s, 1H), 7.76-7.29 (m, 11H), 7.06 (m, 3H), 6.83 (d, 1H), 5.04-4.87 (m, 1H), 4.45-4.15 (m, 1H), 3.94-3.82 (m, 3H), 3.72 (m, 1H), 0.06 (s, 6H); MS 616.6 (M+1), 614.5 (M−1).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:38][C:39]([F:42])([F:41])[F:40])(=O)=O>CN(C)C=O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless oil (50%).
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C([O-])=O)[CH:14]=[CH:13]3)=[N:7][N:6]=1)(=O)=O.[CH3:22][NH2:23].CCOC(C)=O>CS(C)=O>[NH:15]1[C:16]2[C:12](=[CH:11][C:10]([C:8]3[S:9][C:5]([NH:23][CH3:22])=[N:6][N:7]=3)=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3c(ccn3C(=O)[O-])c2)s1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CNc1nnc(-c2ccc3[nH]ccc3c2)s1
Temperature: 110 °C
Yield: 78 %

Procedure:
To a mixture of 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (8 g, 21.11 mmol) in a sealed tube was added methylamine in DMSO (80 mL). The reaction was heated at 110° C. for 1 h and ice-cold water and EtOAc was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 40% EtOAc in Hex) to give 5-(1H-indol-5-yl)-N-methyl-1,3,4-thiadiazol-2-amine (3.8 g, 78%). MS (ESI, pos. ion) m/z: 231 (M+1); 1H-NMR (DMSO-d6, 300 MHz): δ ppm 2.9 (s, 3H), 6.5 (d, 1H) 7.4 (d, 3H) 7.8 (m, 1H), 7.9 (s, 1H), 11.4 (s, 1H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:15]1([NH:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CC(O)C.C1COCC1>[C:15]1([NH:21][CH2:22][CH2:23][NH:24][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCNc1ccccc1
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Oc1ccc([C@H]2CC[C@H](NCCNc3ccccc3)CC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(4-hydroxyphenyl)cyclohexanone (1.0 g, 5.3 mmol) in a mixture of 2-propanol (40 mL) and THF (20 mL) was added N-phenylethylenediamine (0.72 g, 5.3 mmol) and 3 Å molecular sieves. After 3 hours, sodium borohydride (0.27 g, 7.3 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with MeOH, filtered through celite, and the filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (silica, 95:5 CH2Cl2:MeOH) and converted to a maleate salt. Recrystallization from MeOH/Et2O gave trans-4-[4-(2-phenylamino-ethylamino)cyclohexyl]phenol (0.31 g, 14%), as yellow solid: mp 180-184° C.; IR (KBr): 3368, 2945, 2863, 1516 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.40 (br s, 2H), 7.15-7.00 (m, 4H), 6.70-6.55 (m, 5H), 6.02 (s, 2H), 5.65 (br s, 1H), 3.40-3.25 (m, 2H), 3.20-3.10 (m, 3H), 2.45-2.40 (m, 1H), 2.20-2.10 (m, 2H), 1.90-1.80 (m, 2H), 1.50-1.35 (m, 4H); API-MS (m/z): 311 [M+H]+; HPLC: method A, 7.38 minutes (99.1%); method B, 13.29 minutes (99.1%); Anal. Calcd for C20H26N2O.C4H4O4: C, 67.59; H, 7.09; N, 6.57. Found: C, 67.38; H, 7.01; N 6.55.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[NH2:11][OH:12]>CCO>[OH:12][N:11]=[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[NH2:8]
Reactant: NO
Reactant: N#Cc1ccc(CO)cc1
Solvent: CCO
Product: NC(=NO)c1ccc(CO)cc1
Temperature: 74 °C
Yield: 94.9 %

Procedure:
To a solution of 4-(hydroxymethyl)benzonitrile (11.05 g; 83.08 mmol) in EtOH (100 mL) was added hydroxylamine (27.4 mL; 415 mmol) (50% in water) and the mixture was heated to 74° C. for 16 hours. The mixture was poured into a crystallizing dish and the solvent were evaporated. The residue was washed with copious amounts of EtOAc, dry MeOH and dry MeCN which was filtered through a hydrophobic frit and the solvent removed in vacuo to give the title compound as a white solid (13.1 g, 95%). 1H NMR (DMSO-d6, 400 MHz) δ 9.58 (s, 1H), 7.70-7.62 (m, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.79 (s, 2H), 5.23 (t, J=5.6 Hz, 1H), 4.54 (d, J=5.6 Hz, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH2:67])[CH:62]=1)#[N:54]>CN(C=O)C>[C:53]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([NH:67][C:24]([C:19]2[C:20](=[O:23])[O:21][C:22]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:62]=1)#[N:54]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1cccc(NC(=O)c2cc3cccc(OC(F)(F)F)c3oc2=O)c1
Temperature: 25 °C
Yield: 63.4 %

Procedure:
DIEA (0.015 mL, 0.085 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.021 g, 0.077 mmol) and HATU (0.032 g, 0.085 mmol) in 0.45 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′-cyano-biphenyl-3-ylamine (0.015 g, 0.077 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.022 g of product in 63% yield: LCMS (ESI) m/z 451 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH:4]([NH:7]C(C1C=CC=CC=1)C1C=CC=CC=1)C#N.[C:25](=[O:28])([O-])[O-:26].[K+].[K+].[OH-].[K+]>Cl>[CH:22]1[CH:21]=[C:3]([C@H:4]([NH2:7])[C:25]([OH:26])=[O:28])[C:2]([Cl:1])=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC(NC(c1ccccc1)c1ccccc1)c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: N[C@H](C(=O)O)c1ccccc1Cl
Temperature: 25 °C

Procedure:
The above product was dissolved in aqueous hydrochloric acid (6N, 10 ml) and heated at 70° C. for six hours (until exhaustion of the nitrile). The reaction mixture was cooled to room temperature, made basic (pH >10) by addition of solid potassium carbonate, then with aqueous potassium hydroxide (2M, ca. 5 ml). Washing with ether (3×30 mL), followed by titration to pH 6.5 and concentration of the aqueous phase afforded, upon cooling, a white solid, which was recrystallized to afford a near quantitative yield of L-2-chlorophenylglycine. Analysis by HPLC indicated optical purity of >99%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1NC1CCNCC1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2-methoxyphenylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.7 g, 8.8 mmol) in methanol (30 mL) was added 4N hydrochloric acid in ethyl acetate (20 mL) at room temperature. After stirring for 1 h, the resulting suspension was concentrated in vacuo. The residue was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 10-20% methanol in chloroform to furnish 4-(2-methoxyphenylamino)-piperidine (1.8 g, 8.7 mmol, 99%) as white crystals.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[N:5]1)(=O)C.C[O-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[F:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([CH2:14][N:15]3[CH2:24][CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16]3)=[N:5][NH:4]2)=[CH:8][CH:9]=1
Reactant: CC(=O)n1nc(CN2CCc3ccccc3C2)c2ccc(F)cc21
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Fc1ccc2c(CN3CCc4ccccc4C3)n[nH]c2c1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
2-(1-Acetyl-6-fluoro-1H-indazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (300 mg, 0.93 mmol) in CH2Cl2 /MeOH (1:1, 10 mL) was treated with sodium methoxide (2 mg) and stirred for 15 min at 20° C. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (MgSO4), concentrated and purified by flash chromatography (50% EtOAc in hexane) to give the title compound as a colourless oil. Conversion to the hydrogen oxalate salt in MeOH/Et2O gave colourless crystals (202 mg, 59%); mp 200°-201° C. (from MeOH/Et2O); 1H NMR (360 MHz, d6 -DMSO) d 7.93 (dd, J=8.8, 5.3 Hz, 1H, indazole), 7.30 (dd, J=9.7, 2.8 Hz, 1H, indazole), 7.15-6.97 (m, 5H, aromatic), 4.25 (s, 2H, Ar--CH2N), 3.88 (s, 2H, Ar--CH2N), 3.00 (bs, 2H, tetrahydroisoquinoline), 2.89 (bs, 2H, tetrahydroisoquinoline); MS (CI+) m/e 282 (M+H+); Anal. calcd for C17H16FN3. (COOH)2. H2O: C, 65.35; H, 5.33; N, 12.71. Found: C, 65.40; H, 5.24; N, 12.49.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: NCCCCCC(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(O)CCCCCNS(=O)(=O)c1ccc(Cl)cc1

Procedure:
6-Aminohexanoic acid (2.62 g, 0.02 mol) was treated with 4-chlorobenzenesulphonyl chloride (4.22 g, 0.02 mol) by the method described in Example 4 to give the title compound which was recrystallised from ethylacetate-ether (1.92 g, m.p. 126°-7° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[Br:32][C:33]1[C:41]([C:42]#[N:43])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C@H:37]3[C:38]4[C:34](=[C:33]([Br:32])[C:41]([C:42]#[N:43])=[CH:40][CH:39]=4)[CH2:35][CH2:36]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: N#Cc1ccc2c(c1Br)CC[C@@H]2O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reaction time: 0.5 h

Procedure:
A solution of di-tert-butyl azodicarboxylate (3.30 g) in tetrahydrofuran (5 mL) is added dropwise over 45 min to a solution of (S)-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (for preparation see WO 2008001931; 2.10 g), (S)-4-bromo-1-hydroxy-indan-5-carbonitrile (2.40 g) and tri-n-butyl-phosphine (3.8 mL) in tetrahydrofuran (25 mL) at −10° C. The resulting solution is stirred for 30 min and then diluted with ethyl acetate. The resulting solution is washed with water and brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+.
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].[F:10][C:11]1[C:18]([CH3:19])=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:10])[C:18]=2[CH3:19])[C@H:4]1[CH3:8])[CH3:2]
Reactant: Cc1c(F)ccc(C#N)c1F
Reactant: CC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)c(F)c2C)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 2,4-difluoro-3-methylbenzonitrile (340 mg) and lithium carbonate (218 mg), the title compound was obtained as colorless oil (yield: 184 mg, yield: 47%).