Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH2:11]([C:20]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:11]([C:20]1([C:30]([NH:4][C:3]2[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=2[F:10])=[O:31])[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCC1(C(=O)Cl)CCc2ccccc2C1
Reactant: Nc1c(F)cc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC1(C(=O)Nc2c(F)cc(F)cc2F)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 44 h
Yield: 58.3 %

Procedure:
To a solution of 1.0 g (6.8 mmole) 2,4,6-trifluoroaniline and 830 mg (6.8 mmole) 4-dimethylaminopyridine in 40 ml methylene chloride cooled to 5° C. under nitrogen was added a solution of 2.12 g (6.6 mmole) 2-n-nonyl-1,2,3,4-tetrahydro-2-naphthoyl chloride in 10 ml methylene chloride. The resulting solution was stirred at room temperature for 44 hours. Fifty milliters of methylene chloride was then added and the solution was washed sequentially with 30 ml aqueous hydrochloric acid, 30 ml water and 30 ml brine. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue (2.5 g) was purified by column chromatography on silica gel eluting with 2:1 methylene chloride-hexane to yield 1.66 g (58% yield) of the desired product as a white, low melting solid.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]1=[O:15])([O:3]CC)=O.[C:16]1([CH2:22][CH2:23][NH2:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C(C)=CC=CC=1>O>[C:16]1([CH2:22][CH2:23][N:24]2[C:13]3[CH2:12][CH2:11][CH2:10][C:9](=[O:15])[C:8]=3[CH2:7][CH2:6][C:1]2=[O:3])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCC1C(=O)CCCC1=O
Reactant: NCCc1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCCC2=C1CCC(=O)N2CCc1ccccc1

Procedure:
Prepared analogously to Example 27 from 2-(2-carbethoxy-ethyl)-cyclohexan-1,3-dione and 2-phenylethylamine in boiling xylene using a water separator.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:28](O)=[O:29])[N:18]=[C:19]3[CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:41])[C@@H:35]([NH2:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:28]([NH:40][C@H:35]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]([OH:33])=[O:41])=[O:29])[N:18]=[C:19]3[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)CC1
Agent: Cl
Product: CC(C)(C)[C@@H](NC(=O)c1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2c(CC2CCCC2)n1)C(=O)O

Procedure:
50 mg (0.12) of 7-(4-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 430) was reacted with (2S)-amino-3,3-dimethyl-butyric acid methyl ester HCL (24.7 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed by sonication at rt for 3 h and then usual work up as described in general procedure C afforded 54.3 mg of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:35])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:36]([O:38][C:39](=[O:59])[CH2:40][C:41]1([C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)[CH2:43][CH2:42]1)[CH3:37]>>[CH2:36]([O:38][C:39](=[O:59])[CH2:40][C:41]1([C:44]2[CH:49]=[CH:48][C:47]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:35])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=5)=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42]1)[CH3:37]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)Cc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)Cc4ccc(OCc5ccc(C(F)(F)F)cc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-{1-methyl-2-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-ethyl}-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:14](Cl)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(N(CC)CC)C>[C:14]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)(=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC(=O)Cl
Reactant: Nc1ccc2cc[nH]c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2cc[nH]c2c1
Reaction time: 1 h

Procedure:
A solution of 4.24 g. 6-aminoindole in 300 ml. methylene chloride was stirred at 0° C. and 5.4 ml triethylamine followed by 4.2 ml. hexanoyl chloride was then added. The dark mixture was stirred for 1 hour and then filtered to remove a white precipitate. The filtrate was diluted with methylene chloride; washed sequentially with 10% w/v sodium hydrogen sulphate water, and brine; dried (MgSO4); and evaporated. The residue was crystallized from ethyl acetate and hexane to give 6-hexanamidoindole (E) as a white solid. Partial evaporation of the mother liquor gave a second crop of solid giving a combined yield of 4.5 g. (65%); NMR: 0.9 (t, 3H, CH3), 1.4 (m, 4H, CH3CH2CH2), 1.8 (m, 2H, CO.CH2CH2), 2.4 (t, 2H, CO.CH2), 6.5 (m, 1H, H3), 6.8 (dd, 1H, H 5), 7.2 (m, 2H, CO.NH+H2), 7.5 (d, 1H, H4), 8.1 (bs, 1H, H7), 8.3 (br, 1H, NH).
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:71]([NH2:75])([CH3:74])([CH3:73])[CH3:72]>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:75][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:39]
Reactant: CC(C)(C)N
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)(C)C)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and t-butylamine (8.71 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14.8 mg, 46%). LC-MS m/z 595 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13]I)[CH2:6][CH2:5]2.[CH3:29][NH2:30]>O1CCCC1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13][NH:30][CH3:29])[CH2:6][CH2:5]2
Reactant: CN
Reactant: CS(=O)(=O)Nc1cccc2c(C3(CCCI)CCc4cc(F)ccc43)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCCCC1(c2c[nH]c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 49 %

Procedure:
Stir N-{3-[5-fluoro-1-(3-iodo-propyl)-indan-1-yl]-1H-indol-7-yl}-methane sulfonamide (88 mg, 0.17 mmol) and methylamine (40% in water, 2 ml) in tetrahydrofuran (1 ml) at room temperature under nitrogen for 30 minutes. Dilute with dichloromethane and 10% aqueous potassium carbonate. Filter the white solids that crush out and dry under high vacuum to obtain the title compound (35 mg, 49%). LC-MS m/z 416.1 (M++1).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:43])[NH:17][CH2:18][C:19]3[N:20]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]4[C:27]([C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:25]([C:35]([NH2:37])=[S:36])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:45][C:46](=O)[C:47]([O:49][CH2:50][CH3:51])=[O:48].O>C(O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:17][CH2:18][C:19]3[N:20]([CH2:39][CH:40]([CH3:41])[CH3:42])[C:21](=[O:38])[C:22]4[C:27]([C:28]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:26][C:25]([C:35]3[S:36][CH:45]=[C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[N:37]=3)=[CH:24][CH:23]=4)=[O:43])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)Cn1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)c(-c2ccccc2)c2cc(C(N)=S)ccc2c1=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OCC4c5ccccc5-c5ccccc54)c(-c4ccccc4)c3c2)n1
Yield: 70.2 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (Example 194(2)) (2.35 g, 4 mmol) and ethyl bromopyruvate (1.56 g, 8 mmol) in ethanol (20 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-[3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (1.92 g, 70.3%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]#[N+:13][O-])=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>C(Cl)(Cl)Cl>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]#[N:13])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2ccc(C#[N+][O-])nc2c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(Cl)cc(C#N)nc2c1
Temperature: 70 °C

Procedure:
7-Methylquinoline-2-carbonitrile N-oxide (1-4, 5.3 g, 28.8 mmol, 1.0 equiv.) was dissolved in CHCl3 (80 ml, 0.36 M), and POCl3 was added (16.09 ml, 173 mmol, 6.0 equiv.). The mixture was heated to 70° C. overnight, quenched onto crushed ice and extracted three times with dichloromethane. The combined organic layers were washed with water followed by saturated aqueous sodium bicarbonate, dried over MgSO4, filtered and the solvent was removed to yield crude yellow solid. Recrystallization from heptane/EtOAc gave 95 g of 4-chloro-7-methylquinoline-2-carbonitrile (1-5). LRMS m/z (M+H)+203.2 found, 203.6 required.
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[N:10]([CH3:11])[N:9]=[CH:8][C:7]=1[C:12]([O:14]CC)=O)C.[NH3:17]>C(O)C>[CH3:11][N:10]1[C:6]2[N:5]=[CH:4][NH:17][C:12](=[O:14])[C:7]=2[CH:8]=[N:9]1
Reactant: N
Reactant: CCOC=Nc1c(C(=O)OCC)cnn1C
Solvent: CCO
Product: Cn1ncc2c(=O)[nH]cnc21
Reaction time: 40 h

Procedure:
57.2 g. of 5 -[(ethoxymethylene)amino]-1-methyl-1H- pyrazole-4-carboxylic acid, ethyl ester are dissolved in 200 ml. of ethanol, 4.4 g. of ammonia are added and the reaction mixture is autoclaved at 60° for 40 hours. After cooling, the mixture is filtered and the residual 1-methyl-1,5-dihydro-4H-pyrazolo- [3,4-d]pyrimidin-4-one is crystallized from dimethylformamide, m.p. 289°-290° (yield 31 g. - 80.7%).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[C:5](Br)[C:3]=1[NH2:4].[C:10]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:8]=[CH:7][CH:6]=[C:5]([C:17]3[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=3)[C:3]=2[NH2:4])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1c(Br)cccc1Br
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2cccc(-c3ccc(C(C)(C)C)cc3)c2N)cc1

Procedure:
The same procedure as in Example 1(1) was used except that reaction was conducted by using 2,6-dibromoaniline (9.00 g, 35.6 mmol), Pd(PPh3)4 (5.0 g), and 4-t-butylphenyl boronic acid (19.0 g, 107 mmol). Yield 3.0 g. 1H NMR (CD2Cl2): δ 7.50 (d, 4H, Harom), 7.43 (d, 4H, Harom), 7.08 (d, 2H, Harom), 6.83 (t, 1H, Harom), 3.93 (s, 2H, NH2), 1.38 (s, 18H, t-Bu).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([OH:27])=O)[C:11]3[C:16]([CH:17]=[CH2:18])=[N:15][N:14]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1.CN(C)C(=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([C:25]([C:10]2[C:11]3[C:16]([CH:17]=[CH2:18])=[N:15][N:14]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][O:20]4)[C:12]=3[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:27])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c12
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 6-(4-hydroxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.12 g, 6.62 mmol) in tetrahydrofuran (44 mL) were added 1-boc-piperazine (1.35 g, 7.28 mmol), 1-hydroxybenzotriazole (0.09 g, 0.66 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.27 g, 6.62 mmol). After 2 hours, N,N-dimethylacetamide (3 ml), 1-boc-piperazine (0.24 g, 1.32 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.25 g, 1.32 mmol) were added to the reaction mixture. After 1 hour, tetrahydrofuran was evaporated under reduced pressure, water and dichloromethane were then added. The organic layer was washed with an aqueous 1M HCl solution, water, brine, dried (Na2SO4), filtered, concentrated under vacuum. The crude residue was purified on a silica gel column chromatography using a gradient of methanol (0-5%) in dichloromethane to yield the title compound as a yellow foam (3.17 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[N:26][C:25]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH2:1]([O:3][C:4](=[O:22])[C@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:25]2[N:26]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)[C@@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCOC(=O)[C@@](C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)Oc1ccccc1

Procedure:
(R)-3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester were reacted, as described in Example 1, Step D, to provide (R)-2-methyl-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-phenyl}-2-phenoxypropionic acid ethyl ester, shown below, as a colorless oil (54%). 1H NMR (300 MHz, CDCl3): δ 7.59 (d, 1H), 7.37 (d, 1H), 7.24 (t, 2H), 7.13, (d, 2H), 7.09 (t, 1H), 6.96 (t, 1H), 6.83 (d, 2H), 6.82 (d, 2H), 4.21 (t, 2H), 4.19 (q, 2H), 3.26 (d, 1H), 3.12 (d, 1H), 2.95 (t, 2H), 2.35 (s, 3H), 1.39 (s, 3H), 1.21 (t, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.CN(C)C=O.[C:12]1([N:18]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=CC(=O)[NH:21][C:19]2=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Cl:6][C:1]1[CH:2]=[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:19](=[O:20])[N:21]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1cc(-c2ccccc2)n(-c2ccccc2)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1nc(Cl)cc(-c2ccccc2)n1-c1ccccc1
Yield: 34.9 %

Procedure:
Oxalyl chloride (3.1 g, 24.4 mmol) was added to a mixture of N,N-dimethylformamide (1.8 g, 24.6 mmol) in dichloromethane (30 ml) at −5° C. to 0° C. under stirring. After the completion of addition the reaction temperature was allowed to reach 20° C. to 25° C. 1,6-Diphenyluracil (4.0 g, 15.2 mmol) was added in portions to the resulted suspension for 2.5 hrs. The reaction mixture was heated to reflux for 4 hours under stirring and continued stirring for 12 hours at room temperature. The reaction mass was poured onto sodium hydroxide solution (150 ml, 0.25 N) and collected the dichloromethane layer. The dichloromethane layer was washed with hydrochloric acid (200 ml, 0.025N), water and saturated sodium chloride solution successively. The organic extract was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the title compound (1.5 g, 35%, HPLC purity 99.8%), mp: 141-143° C.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12]C)=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO.O>[O:1]1[C:9]2[CH:8]=[C:7]([C:10]([OH:12])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cc2occc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2occc2cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 9.1 %

Procedure:
Methyl furo[3,2-c]pyridine-6-carboxylate (1.55 g, 8.74 mmol) is dissolved in MeOH (30 mL) and H2O (15 mL), treated with 3 N NaOH (6.4 mL) and stirred at rt for 7 h. The mixture is concentrated to dryness, dissolved in H2O (10 mL) and acidified to pH 2 with concentrated HCl. The solution is concentrated to dryness, suspended in a smaller amount of water (7 mL) and the resulting solid collected via filtration (lot A). The filtrate is concentrated, triturated with water (3 mL) and the resulting solid collected via filtration (lot B). The filtrate from lot B is concentrated and carried on without further purification as an acid/salt mixture (lot C). Both lots A and B are dried in a vacuum oven at 50° C. for 18 h to afford 690 mg (48%) for lot A, 591 mg (42%) for lot B and 130 mg (10%) of furo[3,2-c]pyridine-6-carboxylic acid as yellow solids. MS (CI) m/z: 164 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[CH:16][CH:15]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:28](O)=O)[N:8]=2)[N:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N[CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71].O>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][C:22](=[O:27])[C:23]([F:25])([F:26])[F:24])=[CH:18][CH:19]=2)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:28][CH2:65][CH2:66][NH:67][C:68]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:74])[N:8]=2)[N:3]=1
Reactant: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c2nc(C(=O)O)cnc2n1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCc1cnc2nc(N)nc(OCc3ccc(CNC(=O)C(F)(F)F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Carboxylic acid 63 (Example 45, 0.10 g, 0.24 mmol) and PyBOP ((Benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate, 0.12 g, 0.24 mmol) are dissolved in 1 mL dry DMF and stirred at room temperature for 30 min. TEA (50 μL) and tert-butyl 2-aminoethylcarbamate (48 mg, 0.3 mmol) are added. The reaction mixture is stirred for additional 3 h and poured into 50 ml of water. The product is extracted with CH2Cl2, dried over MgSO4 and purified via flash column chromatography using CH2Cl2/MeOH (20:1).
Reaction SMILES: CN(C)[C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[NH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.[C:23](O)(=[O:26])CC>>[CH:23]([C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[NH:5][CH:4]=1)=[O:26]
Reactant: CCC(=O)O
Reactant: CN(C)c1c[nH]c2cccnc12
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1c[nH]c2cccnc12
Reaction time: 1 h
Yield: 32.4 %

Procedure:
A solution of 3-dimethylamino-1H-pyrrolo[3,2-b]pyridine (1.53 g) and hexamethylenetetramine (1.22 g) in 6.68 g of 66% propionic acid was added dropwise to a refluxing solution of 2.44 g of hexamethylenetetramine in 8.92 g of the same solvent. The addition was carried out over a period of one hour and the solution was refluxed 3.5 hours more. The solution was concentrated in vacuo and thereto water (30 ml), ethyl acetate (25 ml), and tetrahydrofuran (20 ml) were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (12 g) using a mixed solvent of dichloromethane and methanol (0.15:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a powder of 3-formyl-1H-pyrrolo[3,2-b]pyridine (0.45 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:33])=[C:21]([CH3:34])[CH:20]=2)=[N:12][C:13]([O:15]CC)=O)[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:12][C:13](=[O:15])[C:24]3[C:19](=[CH:20][C:21]([CH3:34])=[C:22]([O:25][C:26]4[C:27]([CH3:33])=[CH:28][CH:29]=[CH:30][C:31]=4[CH3:32])[CH:23]=3)[N:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=C(Nc1ccc(Oc2c(C)cccc2C)c(C)c1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(C)c(Oc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
Titanium (IV) chloride (0.25 mL, 2.3 mmol) was added to a solution of 1-{[4-(2,6-dimethyl-phenoxy)-3-methyl-phenylamino]-ethoxycarbonylimino-methyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.97 g, 2.1 mmol) and DCE (10 mL), and the resulting mixture was heated to 90° C. for 16 h. The reaction mixture was cooled to room temperature and poured into 50 mL EtOH. The mixture was stirred for 30 min and concentrated to dryness. The solid was and purified by FCC (CH3CN/DCM, gradient 0:100 to 20:80) to provide the titled compound (0.28 g, 32%). MS (ESI): mass calcd. for C23H22N4O4, 418.4; m/z found, 419.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.77 (s, 1H), 8.96 (s, 1H), 8.28 (s, 1H), 7.69 (s, 1H), 7.25 (d, J=7.4 Hz, 2H), 7.18 (dd, J=8.3, 6.7 Hz, 1H), 6.78 (s, 1H), 4.30 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 2.08 (s, 6H), 1.32 (t, J=7.1 Hz, 3H).