Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[CH:23]=[CH:22][N:21](S(C5C=CC=CC=5)(=O)=O)[CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCOCC1>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[CH:23]=[CH:22][NH:21][CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccn(S(=O)(=O)c5ccccc5)c4)C3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc[nH]c4)C3)cc21
Temperature: 100 °C
Yield: 82.2 %

Procedure:
A mixture of 299 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid 3 ml of 1N sodium hydroxide and 10 ml of dioxane was heated at 100° C. for 4 hours, then allowed to cool and neutralized to pH 7 with 10% acetic acid. The solvents were evaporated until a solid formed. This solid was collected, washed with water, methanol and ether and dried, giving 180 mg of the desired product, mp 220° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[N:3]=1.[NH2:16][NH2:17]>N1C=CC=CC=1>[NH:16]([C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[N:3]=1)[NH2:17]
Reactant: NN
Reactant: Clc1ncc2c(n1)-c1ccccc1CC2
Solvent: c1ccncc1
Product: NNc1ncc2c(n1)-c1ccccc1CC2

Procedure:
Crude 2-chloro-5,6-dihydrobenzo[h]quinazoline was heated at 120° C. in a mixture of anhydrous pyridine (20 mL) and anhydrous hydrazine (7 mL) for 4 h. The solvent was removed under vacuum and the residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 2-hydrazinyl-5,6-dihydrobenzo[h]quinazoline as a white solid, 2.16 g. 1H NMR (CDCl3, 300 MHz) 8.27 (d, 1H), 8.20 (s, 1H), 7.35 (m, 2H), 7.21 (d, 1H), 6.42 (s, 1H), 4.00 (br s, 2H), 2.91 (m, 2H), 2.80 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz) 164.29, 160.00, 156.72, 139.87, 132.83, 131.02, 128.25, 127.25, 125.47, 119.03, 28.54, 24.24; MS (ES) 213 (M+H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:9][CH2:8]2)=[N:4][C:3]=1[CH2:10][OH:11].[C:12]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([O:14][CH3:15])=[O:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:8][CH2:9]2)=[N:4][C:3]=1[CH2:10][O:11][C:19]1[CH:20]=[CH:21][C:16]([C:12]([O:14][CH3:15])=[O:13])=[CH:17][CH:18]=1
Reactant: OCc1nc(C2CC2)oc1Br
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2nc(C3CC3)oc2Br)cc1
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-2-cyclopropyl-1,3-oxazol-4-yl)methanol (intermediate D3.1, 0.10 g, 0.46 mmol) in THF (4 ml) was added 4-carbomethoxyphenol (0.11 g, 0.69 mmol), Ph3P (0.18 g, 0.69 mmol) and DIAD (0.13 ml, 0.69 mmol). After 2 h at rt, the reaction was concentrated and purified by flash chromatography (silica, 0-35% EtOAc/hexanes) to give methyl 4-[(5-bromo-2-cyclopropyl-1,3-oxazol-4-yl)methoxy]benzoate. LCMS [M+H]+=352.2.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]([C:14](N)=[O:15])[NH:10][C:11](N)=[O:12]>CN1CCCC1=O>[CH2:1]([N:8]1[C:11](=[O:12])[NH:10][NH:9][C:14]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NNC(N)=O
Reactant: NCc1ccccc1
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c(=O)n1Cc1ccccc1

Procedure:
53.5 g of benzylamine and 59 g of hydrazodicarboxamide in 100 ml of N-methylpyrrolidone are stirred at 175° C. for 4 hours and at 200° C. for 5 hours. The solvent is then distilled off in vacuo, the residue is triturated with 50 ml of 10% strength sodium hydroxide solution, and the resulting residue is filtered off. The filtrate is neutralised with 10% strength hydrochloric acid. A precipitate is thereby formed and is filtered off and washed with water. 67 g (70% of the theoretical yield) of 4-benzyl-1,2,4-triazolidine-3,5-dione are obtained as colourless cyrstals of melting point 185°-188° C. (CH3CN).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[N:18]=[C:17]([C:19]([NH:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:27]=2[C@H:28]2[CH2:33][C@@H:32]([NH:34]C(=O)OC(C)(C)C)[C:31](=O)[C@@H:30]([CH3:43])[CH2:29]2)=[O:20])[CH:16]=[CH:15][C:14]=1[F:44]>CCO.N1C=CC=CC=1>[NH2:34][C@@H:32]1[CH2:33][C@H:28]([C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:21][C:19](=[O:20])[C:17]2[CH:16]=[CH:15][C:14]([F:44])=[C:13]([C:7]3[C:6]([F:5])=[CH:11][CH:10]=[CH:9][C:8]=3[F:12])[N:18]=2)[CH2:29][C@H:30]([CH3:43])/[C:31]/1=[N:4]\[O:2][CH3:3]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CO/N=C1/[C@H](N)C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H]1C
Reaction time: 16 h
Yield: 16 %

Procedure:
A solution of methoxylamine-HCl (1.0 equiv.) and tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate (1.0 equiv.) in EtOH/pyridine (1/1, 0.01 M) was capped and left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and Na2CO3 (sat.). The organic layer was washed with NaCl(sat), dried over MgSO4, filtered, concentrated. The Boc group was removed with 25% TFA/CH2Cl2. After 45 minutes, the volatiles were removed in vacuo and the residue was pumped on for 5 minutes, dissolved in CH2Cl2 and neutralized with TEA. The volatiles were removed in vacuo and after pumping the residue was dissolved in DMSO and purified by RP-HPLC to yield N-(4-((1R,3R,5S,E)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 16% yield. LC/MS (m/z)=484.2 (MH+), Rt=0.64 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 8.57 (s, 1H), 8.47 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.25 (broad doublet, J=4.0, 2H), 8.20 (t, J=8.0, 1H), 7.67-7.74 (m, 1H), 7.42 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 4.04-4.08 (m, 1H), 3.79 (s, 3H), 3.23-3.29 (m, 1H), 2.39-2.45 (m, 1H), 2.11 (d, J=8.0, 1H), 2.10 (d, J=8.0, 1H), 1.90 (q, J=12, 1H), 1.40 (q, J=12, 1H), 1.01 (d, J=4.0, 3H); and N-(4-((1R,3R,5S,Z)-3-amino-4-(methoxyimino)-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 27% yield. LC/MS (m/z)=484.2 (MH+), Rt=0.66 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.57 (s, 1H), 8.47 (d, J=4.0, 1H), 8.35 (dd, J=8.0, 4.0, 1H), 8.20 (t, J=8.0, 1H), 8.08 (broad singlet, 2H), 7.67-7.74 (m, 1H), 7.42 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 3.88-3.92 (m, 1H), 3.80 (s, 3H), 3.22-3.28 (m, 1H), 2.51-2.58 (m, 1H), 2.25 (d, J=12.0, 1H), 1.86 (d, J=12.0, 1H), 1.70 (q, J=12, 1H), 1.62 (q, J=12, 1H), 1.34 (d, J=4.0, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CC=CC=1.[C:33]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34]1>O1CCOCC1>[CH3:1][C:2]1[NH:3][C:4]([CH2:25][O:26][C:33](=[O:39])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Reactant: O=C1CCC(=O)O1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(COC(=O)CCC(=O)O)=C(C(=O)OCC)C1c1ccccc1Cl
Yield: 87.4 %

Procedure:
A mixed solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.3798 g), pyridine (0.791 g) and succinic anhydride (0.1501 g) in dioxane (5 ml) was refluxed for 4.5 hours. The resultant solution was concentrated, acidified with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with dilute hydrochloric acid and water in turn. The diethyl ether extract was back-extracted with an aqueous saturated sodium bicarbonate solution and the aqueous solution was washed with diethyl ether. The aqueous solution was acidified with dilute hydrochloric acid to precipitate crystals. The crystals were collected by filtration, washed with water and then dried to give diethyl 2-methyl-4-(2-chlorophenyl)-6-(3-carboxypropionyl)oxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (419.3 mg), m.p. 130° to 131° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1.BrC1C=[CH:20][C:19]([C:22](C)(C)C)=[CH:18]C=1>>[C:19]([C:6]1[CH:5]=[CH:4][C:3]([N:8]2[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]2)=[CH:2][CH:7]=1)([CH3:22])([CH3:20])[CH3:18]
Reactant: C[C@@H]1CN(c2ccccc2F)CCN1
Reactant: CC(C)(C)c1ccc(Br)cc1
Product: C[C@@H]1CN(c2ccc(C(C)(C)C)cc2)CCN1
Yield: 27 %

Procedure:
The title compound was prepared following the procedure of Intermediate 5 but starting from 1-bromo-4-tert-butylbenzene. Purification by chromatography using dichloromethane/methanol (8/2) as eluent afforded The title compound as a liquid (1.5 g, 27%). M+(ESI): 233.3. HPLC (Condition A), Rt: 2.8 min (HPLC purity: 96.6%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN1C(=O)CCC1>[O:50]1[CH2:51][CH2:52][N:47]([C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:25]=[CH:26][C:27]([C:28]4[CH:29]=[N:30][C:31]5[C:36]([CH:37]=4)=[CH:35][CH:34]=[CH:33][CH:32]=5)=[C:4]3[N:3]=2)[CH2:48][CH2:49]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: C1COCCN1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 185 °C

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (72 μmol, 40 mg), N,N-diisopropylethylamine (220 μmol, 38 μL), NMP (2 mL), and morpholine (220 μmol, 19 μL) was heated to 185° C. in microwave synthesizer for 45 minutes. Upon completion, the reaction was cooled to room temperature and then purified via prep-LC to yield 5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine as brown-yellow solid. LCMS tR=1.29 Min (5 min run, UV254nm). Mass calculated for, M+ 346.1, observed LC/MS m/z 347.2 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCOC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:50])[N:34]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH:35]2[CH2:38][C:39](O)=[O:40])=[CH:31][CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32](=[CH:31][CH:30]=1)[C:33](=[O:50])[N:34]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH:35]2[CH2:38][C:39]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:40]
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
With ice-cooling and stirring, 1.57 g of 1,4-dioxa-8-azaspiro[4.5]decane, 2.3 ml of triethylamine and 2.12 g of diethyl phosphorocyanidate were successively added to a solution of 3.32 g of 6-chloro-2-(4-methoxyphenyl)-3-oxoisoindoline-1-acetic acid in 30 ml of dimethylformamide. The mixture was stirred with ice-cooling for an hour. To the reaction mixture was added 150 ml of ice water and the mixture was allowed to stand to give a crystalline precipitate, which was collected by filtration, washed with water and dried. Recrystallization from ether gave 4.13 g of colorless crystals melting at 156°-157° C.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([C:7]([Cl:24])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a dry nitrogen atmosphere 10 g (0.05 mole) of 2-biphenylcarboxylic acid was dissolved with stirring in 116 ml of dry toluene. Pyridine, 4.2 g (0.054 mole), was then added to the reaction mixture followed by 6.4 g (0.054 mole) of thionyl chloride. The reaction mixture was stirred at room temperature for two hours, then filtered to remove a white precipitate. The toluene was removed from the filtrate under reduced pressure to give [1,1'-biphenyl]-2-carbonyl chloride as a liquid residue, which was used without purification in Step B below.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
138.1 g (1.0 mol) of para-hydroxybenzoic acid were first dissolved in 500 ml of water and 500 ml of isopropanol and this solution was admixed at 0 to 5° C. with 230.0 g of KOH solution (50% strength by weight aqueous solution, 2.05 mol). The resulting pH was 13.5. Metered into this solution over the course of one hour, then, at 0 to 5° C., were 176.6 g (1.0 mol) of nonanoyl chloride, and the batch was stirred for 30 minutes at 0 to 5° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.0. The reaction mixture was subsequently adjusted to a pH of 8 at 0 to 5° C. using 25.0 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 100 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 255.95 g (92.0% of theory). According to HPLC and NMR measurement, the product was free from nonanoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[S:33]([C:36]1[CH:41]=[CH:40][C:39](OC)=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8]C([C@@H](NC(N1CCOCC1)=O)CC1C=CC2C(=CC=CC=2)C=1)=O.[N:48]1([C:54]([NH:56][C@@H:57]([CH:61]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:58]([OH:60])=[O:59])=[O:55])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.C1C=CC(C[C@H]([NH2:85])C(O)=O)=CC=1.N1(C(N[C@@H](CC2C3C(=CC=CC=3)C=CC=2)C(O)=O)=O)CCOCC1>>[N:48]1([C:54]([NH:56][C@@H:57]([CH:61]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C:58]([OH:60])=[O:59])=[O:55])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1.[NH2:85][C:39]1[CH:40]=[CH:41][C:36]([S:33]([N:32]([CH2:44][CH:45]([CH3:47])[CH3:46])[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:58]([C@@H:57]([NH:56][C:54]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)=[O:55])[CH:61]([C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[O:59])(=[O:35])=[O:34])=[CH:37][CH:38]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(S(=O)(=O)N(CC(C)C)[C@H](CO)CCCCNC(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)N2CCOCC2)cc1
Agent: O=C(O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1
Agent: O=C(O)[C@H](Cc1cccc2ccccc12)NC(=O)N1CCOCC1
Product: CC(C)CN([C@H](CO)CCCCNC(=O)[C@@H](NC(=O)N1CCOCC1)C(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using (2S)-2-[(morpholine-4-carbonyl)-amino]-3,3-diphenyl-propionic acid. The (2S)-2-[(morpholine-4-carbonyl)-amino]-3,3-diphenyl-propionic acid derivative was prepared from L-diphenylalanine as described for the preparation of (2S)-2-[(morpholine-4-carbonyl)-amino]-3-naphthalen-1-yl-propionic acid (example 32, step A). The final product was obtained in 28% yield (14 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC=CCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(O)c1ccc(C=Cc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC=CCl
Product: O=C(O)c1ccc(C=Cc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)styryl)benzoic acid (4 mmol) in dichloroethene (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed by TLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfite, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)-styryl)benzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+].Cl>CO.O1CCCC1>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:19])=[O:2])=[CH:10][CH:9]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A 1:2 methanol/tetrahydrofuran (60 mL) solution of (4-benzyloxy-phenyl)-acetic acid methyl ester (1.35 g, 5.27 mmol) was combined with 2M aqueous lithium hydroxide (20 mL) at room temperature and the reaction was stirred overnight. The reaction was acidified to pH 1 with 1N hydrochloric acid and extracted with ethyl acetate (2×50 mL). The organic portions were dried over sodium sulfate and the solvent removed in vacuo to give the title compound as a white crystalline solid (1.25 g, 98%). 1H NMR (300 MHz, CDCl3) δ3.63 (s, 2H), 5.09 (s, 2H), 6.96-6.99 (d, 2H), 7.22-7.25 (d, 2H), 7.3-7.5 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:35]=[CH:34][C:25]2[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:35]=[CH:34][C:25]4[NH:26][C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=4[CH:23]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Temperature: 25 °C

Procedure:
Combined 3-Chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.3015 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (75 mg, 0.367 mmol), 4 N HCl in dioxane (76 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 1.5 hours. Let reaction cool to room temperature and evaporated off solvent. Purified with normal phase and reverse phase chromatography to yield a white solid, 3-Chloro-2-[5-chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. LCMS: m/z=499.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.11 (m, 2H), 7.98 (s, 1H), 7.60 (d, 1H, J=8.1 Hz), 7.52 (d, 1H, J=7.6 Hz), 7.43 (m, 2H), 7.21 (s, 1H), 6.70 (d, 1H, J=8.6 Hz), 6.10 (m, 1H), 4.70 (s, 1H), 2.82 (d, 3H, J=4.8 Hz), 2.35 (m, 2H), 2.06 (m, 2H), 1.32 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 5-bromoindanone (2.2 g, 0.01 mol) in a mixture of methanol (50 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.78 g, 0.02 mol) and the reaction mixture was stirred at room temperature overnight. The solution was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 2.15 g of crude material. 1H NMR (300 MHz, CDCl3) 6 ppm 157 (s, 1 H) 1.87-2.02 (m, 1 H) 2.40-2.59 (m, 1 H) 2.73-2.88 (m, 1 H) 2.95-3.11 (m, 1 H) 5.12-5.25 (m, 1 H) 7.29 (s, 1 H) 7.32-7.43 (m, 2 H). MS (ESI), m/z 416.0 (M+205)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[CH3:23][NH:24][CH:25]1[CH2:29][CH2:28][N:27]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:26]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNC1CCNC1
Product: CNC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and N-methylpyrrolidin-3-amine to give 260. MS: (ESI+)=396.1
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10](=[C:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])[C:11]([F:14])([F:13])[F:12]>>[Cl:20][CH:15]([C:10]1([C:11]([F:12])([F:13])[F:14])[O:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[O:8]1)[C:16]([F:19])([F:18])[F:17]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Reactant: Oc1cccnc1O
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2cccnc2O1

Procedure:
11 g of 2,3-dihydroxypyridine were reacted with 23.5 g of 2,3-dichloro-1,1,1,4,4,4-hexafluoro-2-butene as described in Example 2. After distillation under a high vacuum, the product was obtained in the form of colourless crystals in an amount of 15.5 g (=50% of theory). The NMR spectra showed the following characteristic absorptions: 19F-NMR: -68.5 and -81.6 ppm. 1H-NMR 4.81 ppm.