Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert-butyl ester {CAS-No. [335255-58-0]} (245 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (304 mg, 74%).
Reaction SMILES: [CH3:1]/[C:2](/[CH2:10]O)=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)Cl>[N:24]([CH2:10][C:2]([CH3:1])=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: C/C(=C\c1ccccc1)CO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=Cc1ccccc1)CN=[N+]=[N-]
Temperature: 0 °C
Yield: 88.9 %

Procedure:
To a 100 mL round-bottomed flask equipped with a magnetic stir was added trans-2-methyl-3-phenyl-2-propen-1-ol (2.00 g, 13.5 mmol) and 75 mL of methylene chloride. The solution was then cooled to 0° C. while stirring. Then, triethylamine (2.75 g, 27.0 mmol) is added followed by a dropwise addition of methanesulfonyl chloride (2.34 g, 20.4 mmol) and a two hour stir period. The reaction mixture is washed with water (2×75 mL), dried with sodium sulfate and then concentrated de vacuo. The crude mixture is then dissolved in 75 mL of DMF and then stirred via magnetic stir bar. To this mixture, sodium azide (1.76 g, 27.0 mmol) is added. The reaction mixture is then heated to 80° C. and allowed to stir for two hours. At this time, volatiles are concentrated de vacuo and the resulting residue is purified via column chromatography (1:9 ethyl acetate/hexane) providing (3-Azido-2-methyl propenyl)-benzene (2.08 g, 89%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.36-7.25 (m, 5H), δ 6.53 (s, 1H), δ 3.87 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 129.4, 129.2, 128.9, 128.6, 128.4, 127.1, 59.9, 52.0, 22.3, 16.5 ppm; LRMS (EI) calcd for C10H11N3(M+) 173. found 173.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[CH:29]([C:31]([CH3:33])=[O:32])=[CH2:30]>O1CCCC1>[C:1]([C:4]1([CH2:30][CH2:29][C:31](=[O:32])[CH3:33])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: C=CC(C)=O
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 45 °C

Procedure:
To a stirred warm (45° C.) solution of 62.7 g. (0.3 mole) of 9-carbamoylfluorene in 700 ml. of tetrahydrofuran were added in one portion 30 ml. of a 40% aqueous solution of benzyltrimethylammonium hydroxide. The reaction mixture was stirred at 45° C. for fifteen minutes, and was then diluted by dropwise addition of 24.5 g. (0.35 mole) of methyl vinyl ketone. The reaction mixture was heated at reflux for three hours following complete addition, and then it was cooled to about 30° C. and added to 500 g. of ice. The aqueous reaction mixture was extracted several times with 50% diethyl ether in ethyl acetate, and the extracts were combined, washed with water, with 10% aqueous sodium hydroxide, again with water and then dried. Removal of the solvent by evaporation under reduced pressure afforded a solid which, following crystallization from ethyl acetate, was identified as 46.1 g. of 9-carbamoyl-9-(3-oxobutyl)fluorene. m.p. 125°-128° C.
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH3:11].[B:12](OCC)([O:16]CC)[O:13]CC>O1CCCC1>[B:12]([OH:16])([OH:13])[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1cc(C)c(Br)c(C)c1
Reactant: CCOB(OCC)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(O)O)c(C)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
Magnesium (60.27 mmol) and tetrahydrofuran (30 mL) were put in a three-necked round bottom flask and stirred. To the solution, bromomesitylene (13.07 mmol) was added, and the reaction mixture was heated. After that, bromomesitylene (32.02 mmol) dissolved in tetrahydrofuran (30 mL) was added dropwise to the solution. The reaction mixture was heated and refluxed for 4.5 hours. Then, the mixture was cooled to −78° C. (EtO)3B (111.66 mmol) was added dropwise over 15 minutes. After that, the mixture was warmed to room temperature and stirred for additional 5 hours. Then the mixture was cooled to 0° C. The reaction was quenched by the addition of 1 M hydrochloric acid and stirring for additional 2 hours. The reaction mixture was extracted with diethyl ether three times. The combined extracts was washed with brine and dried over anhydrous sodium sulfate. After the drying, the extract was filtered. The filtrate was concentrated to give a solid, which was recrystallized in benzene to give GA33 (26.10 mmol, yield: 58%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[CH2:1]([NH:8][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(NCc3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from benzylamine and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brown solid (Yield=11%). MS ISP (m/e): 386.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=8.88 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.35-7.25 (m, 3H), 7.35-7.10 (m, 4H), 7.06 (d, 1H), 6.97 (d, 1H), 6.90 (t, 1H), 6.00 (d, 1H), 5.95 (d, 1H), 4.54 (d, 2H), 3.65 (s, 3H), 2.13 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][N:13]=[C:14]=[S:15]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:14](=[S:15])[NH:13][CH3:12])=[C:4]([CH3:10])[C:3]=1[CH3:11]
Reactant: Cc1c(Cl)nnc(NN)c1C
Reactant: CN=C=S
Solvent: ClCCl
Product: CNC(=S)NNc1nnc(Cl)c(C)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
(6-Chloro-4,5-dimethylpyridazin-3-yl)hydrazine (W3.006; 8.00 g) was dissolved in DCM (400 ml) and admixed with methyl isothiocyanate (3.39 g). Subsequently, the mixture was stirred at RT for 24 h and left to stand over the weekend. The precipitate was filtered off, washed with DCM and dried in a drying cabinet at 45° C. 11.25 g of the title compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:12])[CH:7]=1.[Cl:18]N1C(=O)CCC1=O>CC(O)=O>[Cl:18][C:7]1[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(OCc2ccc(F)cc2F)cc[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]ccc(OCc2ccc(F)cc2F)c1Cl

Procedure:
To a solution of 4-[(4-fluorobenzyl)oxy]pyridine-2(1H)-one (from Step 2, Example 74) (1.4 g, 5.9 mmol) in AcOH (25 mL) was added N-chlorosuccinimide (0.95 g, 7.1 mmol) and the reaction mixture was heated at reflux for 2 h. The solvent was removed under reduced pressure. 1H NMR (300 MHz, MeOD) δ 7.63-7.55 (m, 1H), 7.45 (d, J=8 Hz, 1H), 7.07-7.00 (m, 2H), 6.58 (d, J=8 Hz, 1H), 5.31 (d, J=8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][CH:14]([C:16]1[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:18][C:19]([C:28]([O:30][CH3:31])=[O:29])([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=1)[CH3:15]>>[C:35]([O:34][C:32]([N:17]1[CH2:18][C:19]([C:28]([O:30][CH3:31])=[O:29])([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:20]=[C:16]1[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[CH3:15])=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)C(C(C)N)=N1
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)C(C(C)NC(=O)Cc2cc(F)cc(F)c2)=N1

Procedure:
Following General Procedure C above and using 3,5-difluorophenylacetic acid (Aldrich) and 1-tert-butoxycarbonyl-2-(1-aminoethyl)-4-methoxycarbonyl-4-phenylmethyl-2-imidazoline (Example J), the title compound was prepared as an amorphous solid. The reaction was monitored by tlc (Rf=0.34 in 2:1 hexanes/EtOAc) and the product was purified by flash column chromatography.
Reaction SMILES: ClC1C=C(NC2N(C)C(COC3[CH:18]=[C:19]4C(=CC=3)N[C:22](=[O:27])[CH:21]=[CH:20]4)=NN=2)C=CC=1Cl.[NH:29]1[C:37]2[C:32](=[CH:33][C:34]([CH2:38][CH2:39][C:40]3[N:41]([CH3:56])[C:42]([NH:45][C:46]4[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[CH:48][CH:47]=4)=[N:43][N:44]=3)=[CH:35][CH:36]=2)[CH:31]=[N:30]1>>[F:55][CH:53]([F:54])[O:52][C:49]1[CH:50]=[CH:51][C:46]([NH:45][C:42]2[N:41]([CH3:56])[C:40]([CH2:39][CH2:38][C:34]3[CH:33]=[C:32]4[C:37](=[CH:36][CH:35]=3)[N:29]([CH:22]3[CH2:21][CH2:20][CH2:19][CH2:18][O:27]3)[N:30]=[CH:31]4)=[N:44][N:43]=2)=[CH:47][CH:48]=1
Reactant: Cn1c(CCc2ccc3[nH]ncc3c2)nnc1Nc1ccc(OC(F)F)cc1
Reactant: Cn1c(COc2ccc3[nH]c(=O)ccc3c2)nnc1Nc1ccc(Cl)c(Cl)c1
Product: Cn1c(CCc2ccc3c(cnn3C3CCCCO3)c2)nnc1Nc1ccc(OC(F)F)cc1

Procedure:
By a procedure analogous to the synthesis of 6-((5-(3,4-dichlorophenylamino)-4-methyl-4H-1,2,4-triazol-3-yl)methoxy)quinolin-2(1H)-one (Example 276), 5-(2-(1H-indazol-5-yl)ethyl)-N-(4-(difluoromethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-amine (0.131 g, 16%) was synthesized as an off-white gum. LCMS: RT 1.858 min; LCMS (ES-API), m/z 469 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:8]1.[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32]Cl)[CH3:28]>CN(C)C=O>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:8]1)[CH3:28]
Reactant: CCN(CC)CCCCl
Reactant: O=C(Cc1c[nH]c2ccccc12)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCn1cc(CC(=O)OCc2ccccc2)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
At a temperature of about +50° C., 6.2 g (44.9 mMol) of potassium carbonate were added to a solution of 4.0 g (15.1 mMol) of phenylmethyl 1H-indole-3-acetate in 40 ml of dimethylformamide and then at the same temperature a solution of 3.0 g (20.0 mMol) of 3-(diethylamino)propylchloride in 5 ml of dimethylformamid were added dropwise. The mixture was stirred for a further hour at 50° C. and overnight at ambient temperature, heated up to 100° C. again and once more 1.0 g of 3-(diethylamino)propylchloride were added. After stirring for 5 hours at ambient temperature, the mixture was stirred into 300 ml of ice water and extracted exhaustively with diisopropylether. The combined organic extracts were washed with saturated saline solution, dried over magnesium sulphate, clarified with activated charcoal and evaporated down under reduced pressure. A colourless oil was obtained in a yield of 5.37 g (94% of theory) and was used in the following step without further purification.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10](=[O:21])[C:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:22]([C:9]1[C:10](=[O:21])[N:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]2[C:7]([CH:8]=1)=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2-c2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(Cc3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 45.1 %

Procedure:
A mixture of 3-benzyl-5-hydroxy-2-oxo-1-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol), β-alanine (767 mg, 8.6 mmol) and NaOMe solution (13 mL, 6.5 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 13 mg of the title compound. MS: (+) m/z 444.25 (M+1).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:22]([Cl:23])=[CH:21][N:20]([CH3:24])[N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[C:31]([OH:33])=[O:32])=[CH:4][CH:3]=1.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[Cl:23][C:22]1[C:18]([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]([C@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]4[C:31]([OH:33])=[O:32])[N:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([C:41]5[CH:42]=[CH:43][C:38]([C:37]([F:48])([F:47])[F:36])=[CH:39][CH:40]=5)=[CH:35][CH:34]=4)[C:11]=3[CH:12]=2)=[N:19][N:20]([CH3:24])[CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cn1cc(Cl)c(COc2ccc3nc([C@@H]4CCCC[C@@H]4C(=O)O)n(Cc4ccc(Br)cc4)c3c2)n1
Product: Cn1cc(Cl)c(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(-c5ccc(C(F)(F)F)cc5)cc4)c3c2)n1

Procedure:
The title compound was prepared using analogous conditions described in Example 144 using (1S,2R)-2-(1-(4-bromobenzyl)-6-((4-chloro-1-methyl-1H-pyrazol-3-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylic acid and (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. for C33H30ClF3N4O3, 623.08; m/z found, 623.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.81 (d, J=8.3, 2H), 7.76-7.67 (m, 5H), 7.63 (s, 1H), 7.34-7.23 (m, 4H), 5.90 (d, J=17.4, 1H), 5.84 (d, J=17.4, 1H), 5.09-4.99 (m, 2H), 3.75 (s, 3H), 3.70-3.61 (m, 1H), 3.00-2.89 (m, 1H), 2.42-2.28 (m, 1H), 2.25-2.17 (m, 1H), 2.14-2.05 (m, 1H), 2.05-1.94 (m, 1H), 1.88-1.63 (m, 2H), 1.64-1.43 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH3:10][O:11][NH:12][CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:10][O:11][N:12]([CH3:13])[C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 2-(thiophen-3-yl)acetic acid (2.0 g, 14.1 mmol), O,N-dimethylhydroxylamine (1.68 g, 16.9 mmol), EDCI (2.95 g, 15.5 mmol), HOBT (2.15 g, 15.5 mmol), and TEA (3.7 mL, 31 mmol) in anhydrous DCM (50 mL) was stirred at room temperature under nitrogen for two hours. The reaction mixture was diluted with CH2Cl2, and the organic layer was washed with aqueous HCl solution (0.5 mol/L, 30 mL×2), saturated NaHCO3 (30 mL×2) and brine(30 mL), dried over Na2SO4, filtered, and concentrated to give the crude N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (2.0 g, yield 76.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](O)=[O:23])=[CH:16][CH:15]=1>CO>[CH:7]1[C:8]2[C:3](=[C:2]([NH:1][C:22](=[O:23])[CH:21]=[CH:20][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:25])([F:26])[F:12])=[CH:19][CH:18]=3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2cnccc12
Solvent: CO
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12
Temperature: 175 °C

Procedure:
5-Aminoisoquinoline (0.50 g, 3.47 mmol) and 3-[4-(trifluoromethyl)phenyl]acrylic acid (3.47 mmol) were combined in a sealed tube and heated at 175° C. for 16 hours with stirring. The mixture was cooled to room temperature, diluted with MeOH, transferred to a flask, and concentrated under reduced pressure. The residue was triturated with ethyl acetate and filtered to provide the title compound. MS (ESI+) m/z 343 (M+H)+; MS (ESI−) m/z 341 (M−H)−; 1H NMR (DMSO, 300 MHz) rotamers δ 6.68 (d, J 15.9, 1H), 7.29 (d, J 15.9, 1H), 7.60 (d, J 15.9, 1H), 7.80 (m, 1H), 8.25 (d, J 6.8, 1H), 8.57 (d, J 5.8, 1H), 9.35 (s, 1H), 10.36 (s, 1H); Anal. Calcd for C19H13F3N2O+2HCl+0.3H2O: C, 54.25; H, 3.74; N, 6.66. Found: C, 53.90; H, 3.94; N, 7.20.
Reaction SMILES: [CH3:1][C@@H:2]([NH:23]C(=O)OC(C)(C)C)[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH3:22][CH:20]([O:19][C:15]1[CH:14]=[C:13]([O:12][C:9]2[N:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([CH3:1])[NH2:23])=[CH:11][CH:10]=2)[CH:18]=[CH:17][CH:16]=1)[CH3:21]
Reactant: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1cccc(Oc2ccc(NC(=O)[C@@H](C)N)cn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
To a solution of 1,1-dimethylethyl ((1R)-1-methyl-2-{[6-({3-[(1-methylethyl)oxy]phenyl}oxy)-3-pyridinyl]amino}-2-oxoethyl)carbamate (Intermediate 31, 400 mg, 0.96 mmol) in dichloromethane (14 mL) was added TFA (6 mL) portionwise during 15 minutes at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off to afford the title compound (260 mg, 85%) as a grey oil.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][OH:7])[CH:2]=[CH2:3].[CH2:8]1[CH:12]2[CH:13]3C=CC([CH:11]2C=[CH:9]1)C3>>[OH:7][CH2:6][CH2:5][O:4][CH2:1][CH:2]1[CH2:11][CH:12]2[CH2:13][CH:3]1[CH:9]=[CH:8]2
Reactant: C=CCOCCO
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: OCCOCC1CC2C=CC1C2
Temperature: 190 °C

Procedure:
In a 300 mL autoclave equipped with a thermal couple and a mechanical stirrer, a mixture of 2-allyloxyethanol (109.5 g, 1.07 mol) and dicyclopentadiene (35.4 g, 0.27 mol) was stirred and heated to 190° C. The reaction was cooled after 3 h. Three such reactions were run and the reaction mixtures were combined. The mixture was distilled using a short-path distillation column under vacuum at 70° C. at 500 mTorr. The distillate (170 g) was dissolved in a mixture of 250 mL of CH3OH and 150 mL of H2O. Hexane (3×125 mL) was added to the mixture in order to extract out cyclopentadiene impurities. To the remaining methanol/water solution NaCl was added to force the product to oil out from solution. Ethyl acetate (200 mL) was added to extract the oil from water. After the solvents were removed by rotovaporation the product was dried under vacuum. Yield 157 g (58%). 1H NMR (500 MHz, CDCl3): Endo isomer: 6.13 (m, 1H); 5.93 (m, 1H); 3.72 (t, 2H); 3.52 (m, 2H); 3.22 (t, 1H); 3.10 (t, 1H); 2.90 (s, 1H); 2.80 (s, 1H); 2.37 (m, 1H); 2.09 (br s, 1H); 1.82 (m, 1H); 1.43 (d, 1H), 1.26 (d, 1H), 0.50 (d of t, 1H). Exo isomer: 6.10 (m, 1H); 6.07 (m, 1H); 3.75 (t, 2H); 3.36 (m, 2H); 3.50 (t, 1H); 3.40 (t, 1H); 2.80 (s, 1H); 2.74 (s, 1H); 2.09 (br s, 1H); 1.71 (m, 1H); 1.33 (d, 1H), 1.30 (d, 1H); 1.24 (m, partially obscured by endo isomer, 1H); 1.11 (d of t, 1H). Endo/exo ratio by 1H NMR was determined to be 82/18.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)O.[SH:31][CH2:32][C:33]([OH:35])=[O:34]>Cl>[ClH:21].[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[S:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: O=C(O)CS
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(O)c2cccc(Cl)c2)c1
Agent: Cl
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(SCC(=O)O)c2cccc(Cl)c2)c1
Yield: 203.2 %

Procedure:
A mixture of intermediate (17) (0.0269 mol) and mercapto-acetic acid (0.0269 mol) in HCl 6N (150 ml) was stirred and refluxed for 2 hours and brought to room temperature. The solvent was evaporated till dryness, yielding 15 g (96%) of [[[2-amino-5-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methyl]thio]-acetic acid hydrochloride salt (intermediate 18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[NH4+].O>CO.[Fe]>[NH2:14][C:4]1[C:5]([O:12][CH3:13])=[C:6]([CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)cc(N)c1OC
Temperature: 70 °C
Yield: 83.9 %

Procedure:
To a solution of methyl 5-chloro-2-methoxy-3-nitrobenzoate (1.21 g, 4.93 mmol) in methanol (50 ml) at room temperature was added ammonium chloride (2.59 g, 49.2 mmol) followed by deionized water (25 ml). The mixture was heated to 70° C. before the addition of iron (1.65 g, 29.6 mmol). The reaction turned to a dark color over the 2 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (50 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in deionized water (25 ml) and EtOAc (25 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×25 ml). The combined organic extracts were washed with brine (25 ml), dried over MgSO4, filtered and concentrated under reduced pressure to give 892 mg (67%) of the title compound as a viscous brown oil. This material was used without further purification. LC-MS 89%, 1.75 min (3 minute LC-MS method), m/z=216.3/218.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.16 (1H, d, J=2.52 Hz), 6.87 (1H, d, J=2.52 Hz), 4.03 (2H, br. s.), 3.89-3.94 (3H, m), 3.84 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3]1.[CH3:16][N:17]([CH:19](N(C)C)N(C)C)[CH3:18]>>[CH3:16][N:17](/[CH:19]=[C:8]1\[CH2:7][CH2:6][C:5]2[C:4]([C:12]([O:14][CH3:15])=[O:13])=[CH:3][N:2]([CH3:1])[C:10]=2[C:9]\1=[O:11])[CH3:18]
Reactant: COC(=O)c1cn(C)c2c1CCCC2=O
Reactant: CN(C)C(N(C)C)N(C)C
Product: COC(=O)c1cn(C)c2c1CC/C(=C\N(C)C)C2=O
Temperature: 90 °C
Reaction time: 10 h

Procedure:
Methyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (288 mg, 1.39 mmol) was treated with tris(dimethylamino)methane (2.4 mL, 13.9 mmol) and the reaction mixture was stirred at 90° C. for 10 h. Volatiles were removed under reduced pressure and the residue used without further purification.