Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@:2]1([CH3:29])[C@@H:7]([CH3:8])[CH2:6][N:5]([C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]3[O:18][CH2:19][CH2:20][C:10]=23)[CH2:4][C@H:3]1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>CO.[Pd]>[NH2:15][C:14]1[C:9]([N:5]2[CH2:6][C@H:7]([CH3:8])[C@@:2]([OH:1])([CH3:29])[C@H:3]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:4]2)=[C:10]2[CH2:20][CH2:19][O:18][C:11]2=[N:12][CH:13]=1
Reactant: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of tert-butyl [(3R,4S,5S)-4-hydroxy-4,5-dimethyl-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (68 mg, 0.17 mmol) in MeOH (3.0 mL), 10 wt % Pd on carbon (25 mg) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (balloon pressure) for 6 h. The mixture was filtered through a pad of diatomaceous earth (eluted with MeOH), and then concentrated under reduced pressure. The resulting crude product was used directly in the next step without further purification (62 mg, 98%). LCMS calc. for C19H31N4O4 (M+H)+: m/z=379.2. found 379.0.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[Mg].II.[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([O:17][C:18](=[O:26])[C:19](=[O:25])[C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[CH2:12]1.[Cl-].[NH4+]>C1COCC1.O>[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([O:17][C:18](=[O:26])[C:19]([OH:25])([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)[C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1
Reactant: Brc1cccs1
Reactant: CN1CCC[C@@H](OC(=O)C(=O)c2cccs2)C1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1

Procedure:
A solution of 2-bromothiophene (0.092 ml, 0.94 mmol) in THF (2 ml) is added to magnesium (0.576 g, 23.7 mmol) followed by a single crystal of iodine. Additional 2-bromothiophene (2.2 ml, 22.8 mmol) in THF (48 ml) is then added dropwise whilst maintaining a gentle reflux. After the addition is completed the reaction mixture is heated to reflux for 1 hour. This mixture is then added to a solution of oxo-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester (6 g, 23.7 mmol) in THF dropwise with stirring. After the addition is completed the reaction mixture is heated to reflux for 2 hours. After cooling to room temperature saturated aqueous ammonium chloride solution (100 ml) is added followed by water (100 ml). The resulting solution is extracted with ethylacetate (200 ml) and the resulting organic phase extracted with 1 Molar hydrochloric acid (100 ml). Basification of the aqueous layer with sodium carbonate, extraction with ethylacetate, drying over magnesium sulphate, filtration and concentration gives the title product as a brown oil which crystallises on standing.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C:5]1=O)([CH3:3])[CH3:2].[CH2:12]1CC2C(CC(CC2)=O)CC1>>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C:5]1=[CH2:12])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)CC1=O
Reactant: O=C1CCC2CCCCC2C1
Product: C=C1C[C@H](C)CC[C@H]1C(C)C

Procedure:
The title compound was prepared as described in Example 45A substituting (2S,5R)-2-isopropyl-5-methylcyclohexanone, purchased from Aldrich, for 2-decalone.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:28][CH3:29])[CH2:11][N:12]1[C:17](=[O:18])[C:16]([C:19](O)=[O:20])=[CH:15][N:14]=[C:13]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(=O)OCC(C)C.[NH2:38][OH:39]>O1CCCC1>[OH:39][NH:38][C:19]([C:16]1[C:17](=[O:18])[N:12]([CH2:11][CH:10]([O:28][CH3:29])[O:9][CH3:8])[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14][CH:15]=1)=[O:20]
Reactant: COC(Cn1c(-c2ccccc2)ncc(C(=O)O)c1=O)OC
Reactant: NO
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(Cn1c(-c2ccccc2)ncc(C(=O)NO)c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Triethylamine (49.4 ml) was added to a solution of 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-ylcarboxylic acid (97.3 g) in tetrahydrofuran (800 ml) in an ice bath in an argon atmosphere, and isobutyl chlorocarbonate (45.6 ml) was added dropwise thereto at 5° C. or lower, followed by stirring at the same temperature for 1 hour. To the reaction mixture was added a 50% hydroxylamine aqueous solution (422 ml), followed by stirring for 20 minutes. The reaction mixture was separated to layers. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated saline (200 ml), and concentrated. To the residue was added toluene (200 ml), followed by concentration. The resulting crude crystals were washed with isopropyl ether (1000 ml) by heating under reflux for 10 minutes, cooled to room temperature, and crystals were collected by filtration. The collected crystals were dried in vacuo at room temperature overnight to obtain the title compound (93.3 g; yield: 91%) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O.[N:20]1([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:18][C:2]([CH3:1])([CH3:19])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:23]1[CH2:24][CH2:25][N:20]([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:21][CH2:22]1)=[O:9]
Reactant: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CC(C)(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 68 %

Procedure:
Prepared in analogy to example 1 (b) from 2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-benzoic acid (Example A11) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a white crystalline solid (yield 68%). MS (m/e): 463.3 (M+H+, 100%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18]([O:20][C:21](=[O:28])[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:28])[CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:15](=[O:17])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:19]
Reactant: CCOC(=O)CC1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Product: CCOC(=O)C[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C

Procedure:
N-α-CBZ, N- -BOC-L-lysine and ethyl-2-pyrrolidineacetate are condensed by the procedure of Example 1, Step C to give N-α-CBZ, N- -BOC-L-lysyl-(S)-2-pyrrolidine acetic acid ethyl ester. The N-α-CBZ group is removed by hydrogenolysis in ethanol containing one equivalent of acetic acid over 10% palladium on charcoal utilizing the procedure of P. G. Katsoyannis and G. P. Schwartz, Methods in Enzymology, 47, 546 (1974), to give N- -BOC-L-lysyl-(S)-2-pyrrolidineacetic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[C:3]1[C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][C:20]([N:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:21][CH:22]=3)[C:17]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:16]=2[CH:15]=1.[C:44]([CH2:46][C:47]([OH:49])=[O:48])#[N:45]>C(O)(=O)C.C([O-])(=O)C.[NH4+]>[C:44](/[C:46](=[CH:12]\[C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[C:3]([C:14]3[CH:26]=[CH:25][C:24]4[C:23]5[C:18](=[CH:19][C:20]([N:27]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)=[CH:21][CH:22]=5)[C:17]([CH2:42][CH3:43])([CH2:40][CH3:41])[C:16]=4[CH:15]=3)=[CH:4][CH:5]=2)=[CH:8][CH:9]=1)/[C:47]([OH:49])=[O:48])#[N:45]
Reactant: CCC1(CC)c2cc(-c3ccc(-c4ccc(C=O)s4)n3C)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCC1(CC)c2cc(-c3ccc(-c4ccc(/C=C(\C#N)C(=O)O)s4)n3C)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21

Procedure:
As shown in scheme 2, 2,7-dibromo-9,9-diethyl-9H-fluorene (21) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain 2-(7-bromo-9,9-diethyl-9H-fluoren-2-yl)-1-methyl-1H-pyrrole (22). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, 2-(7-bromo-9,9-diethyl-9H-fluoren-2-yl)-1-methyl-1H-pyrrole (22) is reacted with diphenylamine to obtain 9,9-diethyl-7-(1-methyl-1H-pyrrol-2-yl)-N,N-diphenyl-9H-fluoren-2-amine (23a). n-butyl lithium is reacted with 9,9-diethyl-7-(1-methyl-1H-pyrrol-2-yl)-N,N-diphenyl-9H-fluoren-2-amine (23a), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(7-diphenyl-amino-9,9-diethyl-9H-fluoren-2-yl)-5-tributylstannylpyrrole (24a). N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)-5-tributyl-stannylpyrrole (24a) is reacted with 5-bromo-2-thiophene carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (25a). Finally, 5-[N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (25a) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(7-diphenylamino-9,9-diethyl-9H-fluoren-2-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (26a) is obtained.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH3:34]>CN(C=O)C>[CH3:34][N:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
tert-Butyl (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate (120 mg, 0.286 mmol) was dissolved in anhydrous DMF (2.0 mL) under N2 and cooled to 0° C. NaH (60% suspension in mineral oil; 15 mg, 0.372 mmol) was added, and the mixture was stirred for 10 min at 0° C. Iodomethane (23 μL, 0.372 mmol) was added, and the mixture was warmed to ambient temperature and stirred for 1 h. The mixture was quenched with aqueous NH4Cl and extracted with 80% EtOAc/hexanes (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was applied to a silica gel column, and elution with a 15% to 40% to 80% EtOAc/hexanes gradient provided the title compound (108.0 mg, 87%) as a white solid: mp 125-128° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.9 Hz, 2H), 7.38 (d, J=9.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 3.31 (s, 3H), 1.47 (s, 9H); HRMS-FAB (m/z) [M+H]+ calcd for C21H21F3N4O3, 434.156. found, 434.157.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[C:27]2([CH2:30][O:29][CH2:28]2)[CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[C:27]3([CH2:30][O:29][CH2:28]3)[CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1CC2(COC2)N1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCC23COC3)cn1
Yield: 35 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (33 mg, 0.1 mmol) was converted, using 6-oxa-1-aza-spiro[3.3]heptane instead of 3-methoxypropylamine, to the title compound (15 mg, 35%) which was obtained as a colourless gum. MS: m/e=392.3 [M+H]+.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:18][C:19]1[CH:20]=[C:21]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: Cc1nn(-c2ccc(CCN)cc2)c(C)c1I
Product: Cc1ccc(-c2c(C)nn(-c3ccc(CCN)cc3)c2C)cc1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanamine (step 4) and 3,4-dimethylbenzeneboronic acid: MS (ESI) m/z 320 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][N:10]([CH:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CN1CCC(O)CC1
Product: CN1CCC(n2cc(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)c(-c3ccc(Cl)cc3)n2)CC1

Procedure:
The title compound is prepared as described in Example 55 starting from {4-[3-(4chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl)-phenyl]-amine (Example 32) and 1-methyl-piperidin-4-ol.
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1>[N:1]1([C:5]2[N:6]=[CH:7][C:8]([C:23]3([OH:26])[CH2:24][CH2:25][C:20]4([O:27][CH2:17][CH2:18][O:19]4)[CH2:21][CH2:22]3)=[CH:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccc(N2CCC2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(N3CCC3)nc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Yield: 42.1 %

Procedure:
2-azetidin-1-yl-5-bromopyridine (64 mg, 0.30 mmol) was dissolved in dry THF (1.5 mL) and cooled to −78° C., followed by the addition of n-BuLi (0.196 mL, 1.6 M in hexanes). Thirty minutes later, a solution of 1,4-cyclohexanedione mono-ethylene ketal (44.6 mg, 0.286 mmol) in dry THF (0.2 mL) was added dropwise at −78° C. with constant stirring. One hour later, the reaction was quenched with NH4Cl (aq) and slowly warmed to rt. The aqueous layer was extracted with CH2Cl2×3, dried, filtered and concentrated to give a crude, which was purified by flash column chromatography (100% EtOAc) to provide 35 mg (43%) of white solid product. MS (M+H+)=291.1.
Reaction SMILES: O.O.C(O)(=O)C(O)=O.[CH2:9]([O:11][C:12](=[O:37])[CH:13]([O:34][CH2:35][CH3:36])[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][C:17]=1[O:30][CH:31]([CH3:33])[CH3:32])O)[CH3:10]>C(O)(C)C.[Pd]>[CH2:9]([O:11][C:12](=[O:37])[CH:13]([O:34][CH2:35][CH3:36])[CH2:14][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[O:30][CH:31]([CH3:32])[CH3:33])[CH3:10]
Reactant: CCOC(=O)C(OCC)C(O)c1ccc(OCc2ccccc2)cc1OC(C)C
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(O)cc1OC(C)C)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.80 g of Pd/C (10%) and 6.0 g of oxalic acid dihydrate were added under argon to 3.20 g (7.95 mmol) of [rac]-3-(4-benzyloxy-2-isopropoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid ethyl ester [mixture of diastereomers] dissolved in 60 ml of isopropanol. This solution was stirred for 24 hours at room temperature and 50 bar H2. Filtration over dicalite and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9:1 to 1:1) left 0.69 g (29% of theory) of [rac]-2-ethoxy-3-(4-hydroxy-2-isopropoxy-phenyl)-propionic acid ethyl ester as yellow oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:20]([OH:22])=[S:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:22][C:20]([C:11]1[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])[C:18]2[C:13]([CH:12]=1)=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)=[S:21]
Reactant: Cc1ccc2c(c1)cc(C(O)=S)n2S(=O)(=O)c1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=S)c1cc2cc(C)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 1-benzenesulfonyl-5-methylthioindole-2-carboxylic acid (3.5 g), sulfuric acid (10 ml) and methanol (10 ml) was heated under reflux for 12 hours. The reaction mixture was poured into ice-water and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (dichloromethane) to obtain 3.4 g of the desired product as a white crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[C:6]([C:12]([O:14]C)=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:31])[CH2:11][C:10]2[C:5](=[C:6]([C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(C(=O)NC3CCN(C)C3)c1)C(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(NC(=O)c2cccc(C3Nc4c(cccc4C(=O)O)CC3(C)C)c2)C1
Yield: 38.2 %

Procedure:
A mixture of methyl 3,3-dimethyl-2-(3-(1-methylpyrrolidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate (76 mg, 0.18 mmol) in methanol (2.7 mL) and sodium hydroxide aqueous solution (1M, 2.34 mL, 2.34 mmol) was heated to reflux for 1.5 h, LC-MS showed the reaction was complete. The solvent was removed in vacuo and the residue was acidified with 1M hydrochloric acid solution until lots of white solid precipitated, which was collected by filtration and washed with water, dried in vacuo to afford 28 mg of 3,3-dimethyl-2-(3-(1-methylpyrrolidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-8-carboxylic acid as a white solid. Yield: 38%. MS (ESI+APCI) M+1=408.2.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH:2]=[CH2:3].[C:8](=[S:10])=S.C[OH:12]>C(OCC)C>[CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH:2]=[CH2:3].[CH2:1]([N:4]([CH2:5][CH2:6][CH3:7])[C:8](=[S:10])[OH:12])[CH:2]=[CH2:3]
Reactant: CO
Reactant: S=C=S
Agent: C=CCNCCC
Solvent: CCOCC
Product: C=CCN(CCC)C(O)=S
Reaction time: 0.25 h

Procedure:
A quantity of N-Allyl-n-propylamine (12.7 g of a 35% solution in methanol, 0.042 mole) was dissolved in 50 ml of ethyl ether, plus 1.52 g of carbon disulfide (0.02 mole) was charged into a beaker and the reaction mixture in the beaker was allowed to let stand for approximately 15 minutes, after which time the volatiles were stripped off, leaving behind 3.7 g of a solid residue, which was identified by conventional instrumental techniques as being the subject compound.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:23]1[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=1[F:25])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)ccc3F)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.080 g, 0.25 mmol) and (2,5-difluorophenyl)boronic acid (0.048 g, 0.30 mmol) in 1,4-dioxane (2 mL) was added a 1N solution of sodium carbonate in water (0.38 mL, 0.38 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.011 g, 0.015 mmol). The mixture was stirred at 100° C. overnight. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, then concentrated and purified on silica gel (0-25% ethyl acetate/hexane) to give the desired product as a diastereoisomer mixture (54 mg). LCMS calculated for C15H12F2N5OS (M+H)+: m/z=348.1. Found: 348.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16].[CH3:17]C(C)=O.C([O-])([O-])=O.[K+].[K+]>IC.O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[C:3]=1[O:15][CH3:16]
Reactant: CC(C)=O
Reactant: COc1c(Cl)cc(Cl)c(C(=O)O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1c(Cl)cc(Cl)c(OC)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To the phenol 1-7 (10.4 g, 39.1 mmol) in HPLC grade acetone (150 mL) was added K2CO3 (15 g, 108.5 mmol) and iodomethane (5 mL, 80. 3 mmol). The reaction was heated to 60° C. for 22 h. The flask was cooled and then H2O (40 mL) was added and the mixture stirred for 30 min. The volatiles were removed in vacuo and the residue was taken up in CH2Cl2 and H2O. After extracting into CH2Cl2 (×3), the combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated to give the methyl ester 2-2 as an orange oil (9.92 g, 91% yield). 1H NMR (400 MHz, d6-DMSO) δ 0.95 (s, 3H), 8.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([OH:15])([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)[C:11]([F:12])([F:13])[F:14])[O:8][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[C:32]([C:38]([F:39])([F:41])[F:40])[CH:31]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(c1ccc(Oc2ccc(C=O)c(C(F)(F)F)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 64.5 %

Procedure:
To a solution of 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (100 mg, 0.24 mmol, Example 56, step 4) in N′N-dimethylacetamide (1.5 ml) were added 4-fluoro-2-(trifluoromethyl)benzaldehyde (69 mg, 0.36 mmol) and cesium carbonate (234 mg, 0.72 mmol). The mixture was stirred for 17 h at room temperature. Ice water was added and the mixture was extracted with AcOEt. The organic phase was washed with water, dried (MgSO4) and concentrated. The product was purified by column chromatography (silica gel, heptane/AcOEt 3:1) to give the title compound (91 mg) as white foam. MS (m/e, ISP neg. ion)=586.2 [M−H+].