Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10]O.S(=O)(=O)(O)O>>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1
Yield: 56 %

Procedure:
A solution of benzoic acid (30 g; 0.25 mole in MeOH (80 g; 2.5 mole) and conc. sulphuric acid (2.7 ml) was passed through the CMR (10.5 ml/min.; 141°-5° C.; 760 kPa). Excess MeOH was removed by rotary evaporation and the residue poured into water (250 ml) and the product extracted in CCl4. The organic phase was washed with bicarbonate solution, dried over MgSO4, filtered, evaporated, and the product (18.6 g; 56% yield) distilled under reduced pressure; b.p. 109° C./30 mm of Hg. cf ref.3, where a different method of work-up was used, and a yield of 92% was obtained after 4 hours at reflux.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[F:26][C:22]1[CH:21]=[C:20]([S:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[C:7]([CH2:6][CH2:5][C:4]([OH:27])=[O:3])=[CH:8][CH:9]=[CH:10]3)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)CCc1cccc2cc(S(=O)(=O)c3cccc(F)c3)ccc12
Temperature: 25 °C
Yield: 86.3 %

Procedure:
3-[6-(3-Fluoro-benzenesulfonyl)-naphthalen-1-yl]-propionic acid ethyl ester (2.0 g) was dissolved in 25 mL ethanol, and 10 mL of 25% aqueous NaOH was added. The reaction mixture was heated to reflux for one hour, then cooled to room temperature. The ethanol was removed under reduced pressure, and the liquid residue was acidified by addition of 10% aqueous HCl. The mixture was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give a crude oil. The oil was dissolved in warm toluene and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure to give 1.6 g of 3-[6-(3-fluoro-benzenesulfonyl)-naphthalen-1-yl]-propionic acid.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[CH2:26][CH2:25][N:24]([C:35]([O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:36])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.O1CCOCC1>>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:27]1[CH2:26][CH2:25][N:24]([C:35]([O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:36])[CH2:23][CH:22]1[CH2:21][NH:8][C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1F)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To 213 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}oxy)benzoic acid was added 3.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the obtained residue was added chloroform, followed by washing with a saturated aqueous sodium hydrogen carbonate solution (1.0 mL). The organic layer was dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and hexane was added thereto. Then, the precipitate was isolated by filtration. It was dried under reduced pressure to obtain 135 mg of 4-({[4-(2-fluorophenyl)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]carbonyl}oxy)benzoic acid as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.C[Si](Cl)(C)C.[F:15][C:16]1[CH:41]=[CH:40][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27][CH2:28][C:29]3([C:37](Cl)=[O:38])[CH2:35][CH:34]4[O:36][CH:31]([CH2:32][CH2:33]4)[CH2:30]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.Cl>ClCCl>[OH:3][NH:2][C:37]([C:29]1([CH2:28][S:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]3[CH:40]=[CH:41][C:16]([F:15])=[CH:17][CH:18]=3)=[CH:22][CH:23]=2)[CH2:35][CH:34]2[O:36][CH:31]([CH2:32][CH2:33]2)[CH2:30]1)=[O:38]
Reactant: O=C(Cl)C1(CSc2ccc(Oc3ccc(F)cc3)cc2)CC2CCC(C1)O2
Reactant: NO
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NO)C1(CSc2ccc(Oc3ccc(F)cc3)cc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (19.7 mmol, 1.3 equivalents) of hydroxylamine hydrochloride in 9.2 mL (114 mmol, 7.5 equivalents) of dry pyridine at 0° C. is treated with 5.8 mL (45 mmol, 3.0 equivalents) of trimethylsilyl chloride, causing white solids to precipitate. The mixture is allowed to warm to ambient temperature overnight. This mixture is then cooled to 0° C. and treated with a solution of (15.1 mmol) of the product from Step F in 73 mL of dichloromethane causing an exotherm to about 8° C. This mixture is stirred at 0° C. for 30 minutes and at ambient temperature for about one hour. The reaction is then treated with 50 mL of 2N aqueous hydrochloric acid and is stirred at ambient temperature for one hour. The aqueous phase is extracted with dichloromethane and the combined organic phases are washed with 2N aqueous hydrochloric acid (2×50 mL) and water (50 mL). The organic phase is then concentrated to yield the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[CH2:23]Br>CN(C=O)C>[Cl:22][C:19]1[CH:18]=[C:17]2[C:16](=[CH:21][CH:20]=1)[CH2:15][N:12]([S:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:13])=[CH:8][CH:7]=1)(=[O:10])=[O:11])[CH2:23]2
Reactant: Clc1ccc(CBr)c(CBr)c1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Cl)cc3C2)cc1
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a suspension of 60% sodium hydride (3.0 g, 0.125 mmol) in mineral oil in 80 ml of anhydrous DMF (100 ml) was dropwise added a solution of para-toluene sulphonamide (5.6 g, 32.60 mmol) in 30 ml of DMF over 1 hour with vigorous stirring at room temperature. After the addition, the mixture was stirred for 1 hour at room temperature and another 1 hour heating at 90° C. To this mixture was added dropwise a solution of 1,2-bis-bromomethyl-4-chloro-benzene (4 g, 14.18 mmol) in 20 ml of anhydrous DMF at 60° C. and then stirred overnight at room temperature. The resultant mixture was poured onto ice and the resulting precipitate was collected by filtration. The precipitate was washed with 1N hydrochloric acid, 5% sodium carbonate and brine then dried (MgSO4), filtered and evaporated to give 2.8 g of 5-Chloro-2-(toluene-4-sulphonyl)-2,3-dihydro-1H-isoindole as a pale yellow solid. MS: [M+H]+ 308
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([O:15]C(C)C)=[O:14])[CH2:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP(O)(O)=O>O1CCOCC1.[OH-].[K+].CO>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)C1CC(=O)N(Cc2ccccc2)C1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A mixture of isopropyl N-benzylpyrrolidin-2-one4-carboxylate (Example 33, 3.93 g) in dioxane (80 mL), aqueous KOH (2 N, 40 mL) and MeOH (60 mL) was stirred at room temperature for 1 hour. The mixture was then cooled with ice, acidified to pH=4 with H3PO4 and left in a refrigerator overnight. The precipitate was filtered and the filtrate was concentrated to give a yellow oil. The oil was contaminated with dioxane, and therefore was dissolved in aqueous KOH. The solution was extracted with CHCl3 (2×20 mL), and the aqueous layer was acidified with HCl (3 N). It was extracted with CHCl3 (4×30 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give N-benzylpyrrolidin-2-one-4carboxylic acid as a pale yellow oil (2.89 g): 1H NMR (300 MHz) δ 10.77 (br s, CO2H), 7.34 (m, 5 H), 5.17 (d, J=14.9 Hz, 1 H), 4.02 (dd, J=9.4, 3.2Hz, 1 H), 3.98 (d, J=14.1 Hz, 1 H), 2.12-2.71 (m, 4 H); 13C NMR (75 MHz) δ 176.47, 174.32, 135.25, 128.78, 128.46, 127.90, 58.63, 45.69, 29.57, 22.83; MS (FAB), m/e 220 (100, M+H), 174 (40); HRMS (FAB) m/e calcd for (C12H13NO3+H) 220.0974, found 220.0984.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][N:33]=[C:34]=[O:35]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:27]([CH2:28][CH2:29][NH2:30])[C:34]([NH:33][CH3:32])=[O:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN=C=O
Product: CNC(=O)N(CCN)c1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 59.5 %

Procedure:
The title compound from Example 157 (150 mg, 0.00035 mol) was treated with methylisocyanate (22 uL, 21.6 mg, 0.00035 mol) in the same manner as described in Example 158. Purification afforded 100.5 mg (59%) of the title compound as a light red solid (m.p. 124°-133°) LC MS (m/e)=452 (MH+). Rt=1.85 min.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].Br[C:8]1[CH:9]=[C:10]([CH:14]2[O:18][CH2:17][CH2:16][O:15]2)[CH:11]=[CH:12][CH:13]=1.CN(C)C=O.C(N(CC)CC)C>[Cu](I)I.O>[O:15]1[CH2:16][CH2:17][O:18][CH:14]1[C:10]1[CH:9]=[C:8]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=[CH:12][CH:11]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C2OCCO2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
A mixture of ethynyl(trimethyl)silane (36 g, 367 mmol), 2-(3-bromophenyl)-1,3-dioxolane (78 g, 342 mmol), N,N-dimethylformamide (400 mL), and triethylamine (1.1 81 mL, mmol) was bubbled with anhydrous argon for 5 minutes, treated with copper iodide (0.94 g, 4.96 mmol) and dichlorobis(triphenylphosphine) palladium(II) (7.7 g, 11.01 mmol), stirred at 60° C. for 3 hours, cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were combined, dried over MgSO4 and concentrated in vacuo to give {[3-(1,3-dioxolan-2-yl)phenyl]ethynyl}-(trimethyl)silane as a yellow oil (63 g, 256 mmol). The yellow oil was dissolved in MeOH (600 mL) and CH2Cl2 (600 mL), treated with cesium carbonate (91.8 g, 281.6 mmol), stirred at room temperature for 10 h, poured into water and extracted with ethyl ether. The ether extracts were combined, dried over MgSO4, concentrated in vacuo and distilled to give 2-(3-ethynylphenyl)-1,3-dioxolane as a yellow oil (42 g, 71% yield), MS m/e M+ 174; 1H NMR (400 MHz, DMSO-d6) 3.9-4.05 (m, 4H), 4.15 (s, 1H), 5.7 (s, 1H), 7.35-7.45 (m, 4H).
Reaction SMILES: NC1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-])=O>>[NH2:19][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(N)cc2)cc1
Yield: 99 %

Procedure:
(RK1-1-30)I This compound was prepared according to the procedure for compound 12a except using 11d to obtain the required product as an off-white solid (225 mg, 99%). Mp=174-176° C. (lit 190-190.5° C., Bioorganic and Medicinal Chemistry 15(2), 1014-1021; 2007); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.52 (d, J=8.8 Hz, 2H), 6.14 (br s, 1H), 4.00 (br s, 2H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@H:13]1[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25]4)[CH:19]=3)[CH2:14]1)[CH2:6][CH2:5]2.[O:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[CH2:37]OS(C)(=O)=O>>[CH3:31][O:30][CH:27]1[CH2:26][CH2:25][N:24]([CH2:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@@H:13]([N:7]2[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:37][C@@H:33]5[CH2:34][CH2:35][CH2:36][O:32]5)[CH:3]=4)[C:8]2=[O:12])[CH2:22][CH2:21]3)[CH2:29][CH2:28]1
Reactant: COC1CCN(Cc2ccc3c(c2)CC[C@H](N2CCc4cc(O)ccc4C2=O)C3)CC1
Reactant: CS(=O)(=O)OC[C@@H]1CCCO1
Product: COC1CCN(Cc2ccc3c(c2)CC[C@H](N2CCc4cc(OC[C@@H]5CCCO5)ccc4C2=O)C3)CC1

Procedure:
According to method F, 6-hydroxy-2-[(S)-6-(4-methoxypiperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-3,4-dihydro-2H-isoquinolin-1-one was alkylated with methanesulfonic acid (S)-1-(tetrahydrofuran-2-yl)methyl ester. The product was thus obtained with the molecular weight of 504.68 (C31H40N2O4); MS (ESI): 505 (M+H+).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH3:6][N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19](F)(F)F)[CH:14]=2)[C:10](=[O:23])[C:9]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[CH:8]1.[OH2:29]>>[C:19]([C:15]1[CH:14]=[C:13]([C:11]2[C:10](=[O:23])[C:9]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:8][N:7]([CH3:6])[CH:12]=2)[CH:18]=[CH:17][CH:16]=1)([OH:2])=[O:29].[S:1](=[O:3])(=[O:2])([OH:5])[OH:4]
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)c(-n2cccn2)c1
Reactant: O
Agent: O=S(=O)(O)O
Product: Cn1cc(-c2cccc(C(=O)O)c2)c(=O)c(-n2cccn2)c1
Temperature: 140 °C

Procedure:
200 ml (3.74 moles) of concentrated sulphuric acid are added dropwise to 150 g (0.47 mole) of 1-methyl-3-(pyrazol-1-yl)-5-(3-trifluoromethylphenyl)-4-pyridone, with stirring, whereupon the temperature rises to 80° C. to 90° C. When the addition has ended, the mixture is warmed at 140° C., with stirring, until the evolution of gas has ended (about 45 minutes) and is then left to cool to about 40° C. to 50° C., 200 ml of water are carefully added in small portions and, when the addition has ended, the mixture is heated at the reflux temperature for about 60 minutes. The precipitate which separates out of the cooled reaction mixture is filtered off with suction, washed with a little water and dried at 80° C. 148 g (about 80% of theory) of a solid [5-(3-carboxyphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone-sulphuric acid adduct (xn H2SO4)] are obtained, 40 g of which (about 0.1 mole) are dissolved in a mixture of 700 ml of water and 700 ml of ethanol at 70° C. An aqueous barium hydroxide solution is added dropwise to this solution until the pH reaches 7.5, and the barium sulphate precipitated is filtered off with suction over kieselguhr. Solid carbon dioxide is added to the filtrate at room temperature until, at a pH value of 5.5, the free acid precipitates, which is filtered off with suction, washed with a little cold water and dried. 11.5 g (37% of theory) of 5-(3-carboxyphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone of melting point 280° C. are obtained.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3].O[Li].O.Cl>C1COCC1.CO.O>[CH2:1]([C:4]1[N:5]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]2[C:11]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(CC(=O)OCC)c2ccccc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCc1c(CC(=O)O)c2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
tert-Butyl 2-allyl-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (300 ma, 0.87 mmol) was dissolved in 6 mL of THF/MeOH/H2O (3/2/1) and to it was added LiOH.H2O (110 mg, 2.6 mmol). The reaction mixture was allowed to stir at ambient temperature for 20 minutes. The reaction mixture was cooled to 0° C. and acidified with 1N (aq) HCl. The reaction mixture was extracted with ethyl acetate and the organic layer was separated and dried over MgSO4. The mixture was filtered and concentrated to afford 260 mg of 2-(2-allyl-1-(tert-butoxycarbonyl)-1H-indol-3-yl) acetic acid. The acid from the step above (260 mg, 0.82 mmol) was dissolved in 4 mL of DMF, and to it were added 1-(3-bromo-5-fluorobenzyl)-N-(4-chlorophenyl)-N-methylhydrazinecarboxamide hydrochloride (0.74 mmol) and N,N-diisopropylethylamine (427 μL, 2.5 mmol). The reaction mixture was cooled to 0° C. and HATU (343 mg, 0.9 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for two hours and then was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl, saturated aqueous NaHCO3 and brine. The organic layer was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford 418 mg of tert-butyl 2-allyl-3-(2-(2-(3-bromo-5-fluorobenzyl)-2-(4-chlorophenyl)(methyl)carbamoyl)hydrazinyl)-2-oxoethyl)-1H-indole-1-carboxylate as a white solid. MS (m/z): 685.1 [M+H]+; HPLC retention time 5.14 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]2[NH:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]([CH3:38])[CH:26]=3)=[CH:24][C:17]=12)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]([CH3:38])[CH:26]=[C:25]2[C:23]1[NH:22][C:18]2=[N:19][CH:20]=[CH:21][C:16]([CH2:15][NH:6][S:7]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)(=[O:9])=[O:8])=[C:17]2[CH:24]=1
Reactant: COc1ccc(CN(Cc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)S(=O)(=O)c2cccs2)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc2c(-c3cc4c(CNS(=O)(=O)c5cccs5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 32.8 %

Procedure:
Thiophene-2-sulfonic acid [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is prepared as described in Example 210 starting with 0.1 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide instead of the N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-4-trifluoromethoxybenzenesulfonamide used in Example 210 and 0.110 g of para-toluenesulfonic acid. 0.025 g of thiophene-2-sulfonic acid [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is obtained, the characteristics of which are as follows:
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][NH:27][NH2:28]>C(O)C>[NH2:10][C:6]1[NH:28][N:27]([CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[F:23])[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccccc1F
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2F)[nH]1
Reaction time: 2 h

Procedure:
30.2 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 2 g of p-toluenesulphonic acid were dissolved in 300 ml of ethanol and 27.1 g of o-fluorobenzylhydrazine were added under nitrogen. After stirring for two hours, the mixture was left to stand overnight and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 146°, 11 g (27%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C@@H:12]([N:19]2[CH2:23][C:22]([O:24][CH3:25])=[CH:21][C:20]2=[O:26])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>O1CCCC1.O.ClCCl>[CH:14]1([CH2:13][C@H:12]([N:19]2[CH2:23][C:22]([O:24][CH3:25])=[CH:21][C:20]2=[O:26])[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[CH:5][N:6]=2)=[O:27])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)[C@H](CC2CCCC2)N2CC(OC)=CC2=O)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccc(C(=O)O)cn2)C1
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A solution of 6-[(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-nicotinic acid methyl ester (prepared as in Example 10, 62 mg, 0.16 mmol) in tetrahydrofuran (2 mL) was treated with a solution of lithium hydroxide monohydrate (8 mg, 0.18 mmol) in water (1 mL). The mixture was stirred for 1 h. It was then acidified with 2N aqueous hydrochloric acid and diluted with dichloromethane, washed with saturated sodium chloride solution and dried to afford 6-[(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-nicotinic acid, (23 mg, 39%) as a white powder: LR-ES-MS m/z calculated for C19H23N3O5 [M]+ 373, observed [M+H]+ 374; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.97 (m, 11H) 3.79 (s, 3H) 4.01 (d, J=17.9 Hz, 1H) 4.33 (d, J=17.7 Hz, 1H) 4.93 (dd, J=10.9, 4.5 Hz, 1H) 5.18 (s, 1H) 8.12 (d, J=8.5 Hz, 1H) 8.24 (dd, J=8.7, 2.3 Hz, 1H) 8.83 (d, J=2.3 Hz, 1H) 11.18 (s, 1H) 12.81 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]([NH:15]C(C)(C)C)=[O:14])=[NH:11].[ClH:20]>>[ClH:20].[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]([NH2:15])=[O:14])=[NH:11]
Reactant: Cc1cccc(C)c1NC(=N)NC(=O)NC(C)(C)C
Agent: Cl
Product: Cc1cccc(C)c1NC(=N)NC(N)=O

Procedure:
A mixture of 25.7 g. (0.106 moles) of 1-(2,6-dimethylphenylamidino) -3-(t-butyl)urea and 200 ml. of conc. hydrochloric acid is refluxed for 1/2 hour. The reaction mixture is cooled, the solid filtered and washed with 10 ml. of 1:1 HCl/H2O and dried. The product is then recrystallized from ethanol-ether to obtain (2,6-dimethylphenylamidino)urea hydrochloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][CH3:11])[CH3:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH4+:15].[OH-].CCOC(C)=O.O>C1COCC1>[CH3:11][O:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)[CH3:9]
Reactant: COC(C)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.4 %

Procedure:
1-fluoro-4-(1-methoxyethyl)-2-nitrobenzene (664 g, 3.33 mmol) was stirred in THF (10 ml). NH4OH (0.39 ml, 10.0 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. Further 780 ul of NH4OH was added and the reaction mixture was heated at 120° C. for 10 minutes using microwave (Biotage Initiator) and then at 140° C. for 50 minutes. After cooling to room temperature, the reaction mixture was poured into EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The resulting material was purified by flash chromatography on silica eluting with 0% to 50% EtOAc/Hexane to afford the title compound (290 mg, yield: 44%). 1H-NMR (400 MHz, CDCl3) δ 1.42 (d, 3H) 3.22 (s, 3H) 4.24 (q, 1H) 6.05 (br. s., 2H) 6.83 (d, 1H) 7.38 (dd, 2.01 Hz, 1H) 8.04 (d, 1H)