Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1COCC1.C([Si](C(C)C)(C(C)C)[S-])(C)C.[Li+].[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]2[C:52]3[CH:58]=[CH:57][C:56](I)=[CH:55][C:53]=3[O:54][C:48]=2[C:47]1([CH3:61])[CH3:60])=[O:45])([CH3:42])([CH3:41])[CH3:40]>O1CCOCC1.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:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C:49]2[C:52]3[CH:58]=[CH:57][C:56]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])=[CH:55][C:53]=3[O:54][C:48]=2[C:47]1([CH3:61])[CH3:60])=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCc2c(oc3cc(I)ccc23)C1(C)C
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Si]([S-])(C(C)C)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)[Si](Sc1ccc2c3c(oc2c1)C(C)(C)N(C(=O)OC(C)(C)C)CC3)(C(C)C)C(C)C
Reaction time: 2.5 h
Yield: 130.3 %

Procedure:
Anhydrous dioxane was bubbled with Argon for 1 h before being used. Triisopropylsilanethiol (4.00 mL, 18.6 mmol) was dissolved into anhydrous 1,4-dioxane (15 mL) and a solution of lithium hexamethyldisilazide in THF (1.0 M 17.7 mL, 17.7 mmol) was added slowly. The reaction was stirred for 2.5 h. A portion of the lithium triisopropylsilanethiolate solution (15.4 mL, 7.70 mmol) was added to a suspension of 7-iodo-1,1-dimethyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (3.00 g, 7.02 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.81 g, 0.70 mmol) in 1,4-dioxane (10 mL) under argon. The reaction mixture was stirred at 60° C. for 2 h and the solvent was evaporated. The residue was triturated with anhydrous hexane, filtered through a plug of Celite and the filtrate was concentrated down to yield 4.48 g of 1,1-dimethyl-7-triisopropylsilanylsulfanyl-3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester. This product was used in the next step without further purification. MS m/z 490 [M+H]+
Reaction SMILES: CN(C)CCC(OC(C(O)CCCCCCC/C=C\C/C=C\CCCCC)CCCCCCC/C=C\C/C=C\CCCCC)=O.[CH3:46][N:47]([CH3:91])[CH2:48][CH2:49][CH2:50][C:51]([O:53][CH:54]([CH:72]([OH:90])[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH:80]=[CH:81][CH2:82][CH:83]=[CH:84][CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH:62]=[CH:63][CH2:64][CH:65]=[CH:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[O:52]>>[CH3:91][N:47]([CH3:46])[CH2:48][CH2:49][CH2:50][C:51]([O:53][CH:54]([CH:72]([OH:90])[CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79]/[CH:80]=[CH:81]\[CH2:82]/[CH:83]=[CH:84]\[CH2:85][CH2:86][CH2:87][CH2:88][CH3:89])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]/[CH:62]=[CH:63]\[CH2:64]/[CH:65]=[CH:66]\[CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[O:52]
Reactant: CCCCCC=CCC=CCCCCCCCC(O)C(CCCCCCCC=CCC=CCCCCC)OC(=O)CCCN(C)C
Agent: CCCCC/C=C\C/C=C\CCCCCCCC(O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCN(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCC(O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCCN(C)C
Yield: 31 %

Procedure:
Using an analogous procedure to that described for the synthesis of (6Z,9Z,27Z,30Z)-19-hydroxyhexatriaconta-6,9,27,30-tetraen-18-yl 3-(dimethylamino)propanoate, 6Z,9Z,27Z,30Z)-19-hydroxyhexatriaconta-6,9,27,30-tetraen-18-yl 4-(dimethylamino)butanoate was obtained as a colorless oil (218 mg, 31%). 1H NMR (400 MHz, CDCl3): δ 5.44-5.29 (m, 8H), 4.92-4.81 (m, 1H), 3.71-3.54 (m, 1H), 2.81-2.75 (m, 4H), 2.46-2.34 (m, 1H), 2.28 (s, 3H), 2.27 (s, 3H), 2.09-2.02 (m, 8H), 1.94-1.78 (m, 2H), 1.69-1.20 (m, 36H), 0.93-0.86 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11]([O:14][CH3:15])(=[O:13])[CH3:12].C[O-].[Na+].S(=O)(=O)(O)O>CCCCCCC.C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:4]([CH:3]([CH2:8][CH2:7][CH2:6][CH3:9])[CH2:15][O:14][C:11](=[O:13])[CH:12]=[CH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:5]
Reactant: COc1ccc(C=O)cc1
Reactant: COC(C)=O
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CCCCC(CC)COC(=O)C=Cc1ccc(OC)cc1
Yield: 83 %

Procedure:
U.S. Pat. No. 5,527,947 describes a process in which C1-C4-alkoxybenzaldehydes, such as anisaldehyde, and C1-C4-alkyl acetates, such as methyl acetate, are dissolved in an inert hydrocarbon, such as heptane, toluene or petroleum ether. In the presence of a strongly alkaline metal base, such as sodium methoxide, the feed substances react to give a mixture of the corresponding C1-C4-alkyl-C1-C4-alkoxy cinnamates, the alkali metal salts of the corresponding C1-C4-alkoxy cinnamic acid and the C1-C4-alkanols. Following acidification of the reaction mixture with a strong polybasic acid, such as sulfuric acid, the liberated acetic acid is esterified with the C1-C4-alkanoles and distilled off. The mixture of C1-C4-alkyl-C1-C4-alkoxycinnamates and C1-C4-alkoxycinnamic acids which remains is reacted with a C5-C14-alkanol in the presence of a metal salt of a strong polybasic acid, such as sulfuric acid. Following transesterification and esterification, the corresponding C5-C14-alkyl-C1-C4-alkoxycinnamate, e.g. 2-ethylhexyl-4-methoxycinnamate, is obtained with 83 to 87% yield.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.ClC1C2C(=CC=C(I)C=2)N=CN=1.[NH2:37][C:38]1[CH:39]=[C:40]2[C:44](=[CH:45][CH:46]=1)[NH:43][CH:42]=[CH:41]2>C(Cl)Cl.CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)(C)C>[NH:43]1[C:44]2[C:40](=[CH:39][C:38]([NH:37][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)=[CH:46][CH:45]=2)[CH:41]=[CH:42]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Agent: Clc1ncnc2ccc(I)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Ic1ccc2ncnc(Nc3ccc4[nH]ccc4c3)c2c1
Temperature: 60 °C
Yield: 42.3 %

Procedure:
6-Iodo-3H-quinazolin-4-one (50 gm, 18.3 mmol) was slurried in 60 mL methylene chloride (CH2Cl2) with several drops of DMF. Oxalyl chloride (6.99 g, 4.83 mL, 55.1 mmol) was added dropwise to the slurry at 0° C. The reaction was refluxed for 48 hours and then concentrated in vacuo. Pyridine (2.9 gm, 2.97 mL, 36.7 mmol) and tert-butyl alcohol (10 mL) was added to dissolve the 4-chloro-6-iodo quinazoline. 5-Aminoindole (2.9 gm, 22.0 mmol) was added and the reaction was heated to 60° C. overnight. Diluted the reaction mixture with chloroform (CHCl3) and washed with brine, saturated aqueous NaCHO3 and dried over NaSO4. The organic layer was concentrated in vacuo to a black oil. The crude product was chromatographed on silica gel (2 parts methanol to 1 part methylene chloride (2 MeOH/CH2Cl2)) to provide 2.99 gm of white crystalline product.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10].[Br:15][C:16]1[N:20]2[N:21]=[C:22](F)[CH:23]=[CH:24][C:19]2=[N:18][CH:17]=1.CCN(C(C)C)C(C)C>CC(O)C>[Br:15][C:16]1[N:20]2[N:21]=[C:22]([N:6]3[CH2:7][CH:2]4[CH2:8][CH:5]3[CH2:4][N:3]4[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH:23]=[CH:24][C:19]2=[N:18][CH:17]=1
Reactant: Fc1ccc2ncc(Br)n2n1
Reactant: CC(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CC2CC1CN2c1ccc2ncc(Br)n2n1
Yield: 100.2 %

Procedure:
A solution of (1S,4S)-isopropyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate hydrochloride (0.9 g, 4.2 mmol), 3-bromo-6-fluoroimidazo[1,2-b]pyridazine (1.0 g, 4.6 mmol), and Hunig's base [7087-68-5] (3.0 mL, 17.2 mmol) in 2-propanol (21 mL) was stirred at reflux under N2 blanket for 3d then partitioned between brine and ethyl acetate. The extract was dried (MgSO4) and evaporated to obtain 1.6 g of yellow solid. LRMS (ESI) m/z 380.0/382.0 [(M+H)]+, calc'd for C16H18BrN6O2: 380.24.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[C:15]=1[C:16](O)=[O:17]>>[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=441.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methylsulfanyl-4,6-bis-trifluoromethyl-benzoic acid (CAS 896120-49-3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11][C:10]=1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][C:23](=O)[CH2:24][CH3:25]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:17][CH:22]=[C:23]([CH2:24][CH3:25])[N:16]=2)=[CH:11][C:10]=1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(C(N)=S)ccc1OCc1ccccc1
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4-benzyloxy)-3-propylbenzenecarbothioamide (0.53 g, 1.86 mmol) (Example 31) in EtOH (70 mL) was added 1-bromo-2-butanone (0.47 g, 2.79 mmol), and the reaction was stirred for 3 h at 70° C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was saved. This procedure was repeated on a 1.1 g scale (based on thioamide). The two crude residues were combined and purified by silica gel chromatography (EtOAc/hexane (v/v)=1:9, then 100% EtOAc) to give 0.87 g (67% overall) of the title compound. 1H NMR (400 MHz, CDCl3):δ 7.72 (s, 1H), 7.67 (d, 1H), 7.45-7.28 (m, 5H), 6.88 (d, 1H), 6.76 (s, 1H), 5.12 (s, 2H), 4.09 (q, 2H), 2.84 (q, 2H), 2.75-2.66 (m, 2H), 1.30 (t, 3H), 0.93 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:26][C@H:27]4[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]4)[C:15]([N:17]4[CH2:22][CH2:21][O:20][C@@H:19]5[CH2:23][CH2:24][CH2:25][C@@H:18]45)=[N:16][C:12]=3[CH:11]=[C:10]([C:34]#[N:35])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[Li+].CC1(C)CCCC(C)(C)N1[Mg]Cl.[Br:50]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[Br:50][C:11]1[C:12]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][C@@H:19]4[CH2:23][CH2:24][CH2:25][C@@H:18]34)[N:14]([CH2:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]3)[C:13]=2[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:9][C:10]=1[C:34]#[N:35]
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3c(Br)c(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (Example 3.2, Step 3; 300 mg, 0.611 mmol) in THF (8 mL) was added 2,2,6,6-tetramethylpiperidinylmagnesium chloride lithium chloride complex (Aldrich, 1M in THF/toluene) (1.22 mL, 1.22 mmol). The resulting yellow solution was stirred at −78° C. for 45 minutes, and then 1,3-dibromo-5,5-dimethylhydantoin (437 mg, 1.527 mmol) was added as a solid in one portion. The reaction was allowed to warm slowly to 0° C. over 90 minutes and then quenched with saturated NH4Cl (10 mL). EtOAc (75 ml) was added, and the organic layer was washed with water and brine (25 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column eluting with 0 to 50% EtOAc/DCM afforded 7-bromo-4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd for C27H30BrClN6O [M+H]+=571. found=571.
Reaction SMILES: [F:1][C:2]1([F:34])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:30]C)=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:32])=[C:19]([CH3:33])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Si](I)(C)(C)C.CO>CC#N>[F:34][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([OH:30])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:32])=[C:19]([CH3:33])[CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc(C)c1C
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: Cc1cnc(O)c(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc(C)c2C)c1
Yield: 92.3 %

Procedure:
To a suspension of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (75 mg, 0.16 mmol) in CH3CN (3 mL) was added TMSI (46 uL, 0.30 mmol) dropwise at 20° C. The reaction was stirred at 50° C. for 30 min) MeOH (1.0 mL) was added and the solution was re-partitioned between EtOAc and H2O, washed with NaHSO3 (2×), brine, dried over MgSO4 and evaporated to dryness to yield a white solid. The crude material was further purified by column chromatography (0-10% MeOH-EtOAc) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (67 mg, 92%). 1H NMR (400 MHz, MeOD) 7.89 (s, 1H), 7.31-7.27 (m, 2H), 7.23-7.19 (m, 2H), 7.12 (d, J=8.3 Hz, 1H), 2.25 (s, 3H), 2.03 (s, 3H), 1.97 (s, 3H), 1.56 (dd, J=3.9, 7.0 Hz, 2H), 1.13 (dd, J=3.8, 6.9 Hz, 2H). Retention time: 1.52 min; ESI-MS m/z calc. 453.4. found 454.5 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C([O-])(O)=O.[Na+].O>[N:10]([CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])=[C:13]=[O:15]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CCN=C=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 93.8 %

Procedure:
β-Alanine tert-butyl ester hydrochloride (13.0, 71.6 mmol) in CH2Cl2 (240 mL) and saturated NaHCO3(aq) solution (240 mL) was degassed and the flask was cooled in ice water bath. Triphosgene (21.2 g, 71.6 mmol) was added in one portion under inert atmosphere at 0° C. The reaction stirred at 0° C. to RT over 2.5 hr. The reaction was diluted with water (500 mL) and poured into reparatory funnel. The layers separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude tert-butyl 3-iso cyanatopropionate (11.5 g) as a yellow liquid. This crude material was directly used for next reaction without purification. 1H NMR (300 MHz, CDCl3): δ 3.53 (t, 2H), 2.52 (t, 2H), 1.47 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:21])[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[C:15]([NH2:19])=[C:14]([Cl:20])[CH:13]=3)[O:11][C:6]=2[C:5]([F:22])=[C:4]([CH2:23][O:24][C:25](=[O:28])[CH2:26]Cl)[C:3]=1[F:29].Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:21])[CH:9]=[C:10]([C:12]3[CH:13]=[C:14]([Cl:20])[C:15]([NH2:19])=[C:16]([Cl:18])[CH:17]=3)[O:11][C:6]=2[C:5]([F:22])=[C:4]([CH2:23][O:24][C:25](=[O:28])[CH2:26][N:32]([CH3:33])[CH3:31])[C:3]=1[F:29]
Reactant: Nc1c(Cl)cc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1Cl
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3cc(Cl)c(N)c(Cl)c3)oc2c1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
2.00 g (4.31 mmol) of Compound 171 obtained in Example 171 was dissolved in 80 mL of dimethylformamide, 1.76 g (21.6 mmol) of dimethylamine hydrochloride and 3.75 mL (21.6 mmol) of diisopropylethylamine were added, and the mixture was stirred at 50° C., for 3 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=9:1), to give 1.68 g of Compound 172 (yield: 83%).
Reaction SMILES: [CH2:1]([C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]([CH:8]([C:14](OCC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])[CH2:2][CH2:3][CH3:4].C1(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)C=CC=CC=1>>[CH2:19]([C:5]1([CH2:1][CH2:2][CH2:3][CH3:4])[C:23]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]([OH:15])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]1=[O:7])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCC(CCCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Yield: 21 %

Procedure:
The title compound (1.2 g, 21%) was prepared following the procedure of Example 1F, substituting the product of Example 4E for the product of Example 1E. 1H NMR (300 MHz, CDCl3): δ 15.16 (d, J=13.97 Hz, 1 H), 8.22 (m, 1 H), 7.59 (m, 2 H), 7.36 (m, 2 H), 4.47 (m, 2 H), 2.25 (m, 2 H), 1.92 (m, 2 H), 1.71 (m, 2 H), 1.50 (m, 2 H), 1.24 (m, 2 H), 1.11 (m, 2H), 0.89 (m, 1 H), 0.65 (m, 7 H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:27][CH2:28]2)=[O:21])[CH2:17][CH2:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182(A), 0.30 g, 0.67 mmol) and methanesulfonyl chloride (0.10 g, 0.88 mmol) in pyridine (3 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 80:20 to 35:65) to give the title compound (0.13 g, 41%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(Br)c1
Product: O=C(OCc1ccccc1)c1cccc(Br)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 7 using 3-bromobenzoic acid instead of 3-bromophenol and benzyl bromide instead of 1-bromopentane.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH2:29])[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Cl:39][C:40]1[C:41]([F:49])=[N:42][C:43]([F:48])=[C:44]([F:47])[C:45]=1F>C(#N)C.CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([NH:13][C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:28][NH:29][C:45]3[C:44]([F:47])=[C:43]([F:48])[N:42]=[C:41]([F:49])[C:40]=3[Cl:39])[CH2:20][CH2:21]2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: Fc1nc(F)c(Cl)c(F)c1F
Reactant: NCc1ccccc1N1CCN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2CNc2c(F)c(F)nc(F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
4-(2-Aminomethyl-phenyl)piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol, prepared in Example 26b) was dissolved in 500 μL of acetonitrile. Then, triethylamine (20 μL, 0.14 mmol) was added, followed by 3-chloro-2,4,5,6-tetrafluoropyridine (17 μL, 0.15 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was diluted to 2 mL in volume with methanol and the mixture was purified by reverse phase HPLC to give 15 mg of the product as a white solid. 1H NMR (CDCl3) δ 7.88 (s, 2H), 7.52 (s, 1H), 7.31-7.38 (m, 2H), 7.15-7.22 (m, 2H), 6.70 (s, 1H), 5.88 (br t, 1H), 4.85 (dd, 2H), 3.71 (m, 4H), 3.02 (t, 4H) ppm.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[F:12][C:13]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:11][C:4]1[C:3]([OH:2])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:13]=1[F:12])=[O:16]
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: COc1cccc(OC)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(C(=O)c2cccc(F)c2F)c(O)c1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 4 g of 2-chlororesorcinol dimethyl ether and 3.7 g of 2,3-difluorobenzoyl chloride in 60 ml of 1,2-dichloroethane at 5° C., 3.06 g of AlCl3 is added in portions. The mixture is allowed to warm to room temperature and then refluxed for 30 minutes. The reaction mixture is poured into concentrated HCl-ice and is permitted to stand about 72 hours. The aqueous layer is extracted with additional organic solvent, dried over Na2SO4 and evaporated to give 3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzophenone, mp 161°-162° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CO.[N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[N+:27]=[N-:28]>CN(C)C=O.[Cu]I>[C:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:28]=[N:27][N:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:1])[CH3:3])=[O:23])[CH2:8][C@@H:9]1[CH3:22])(=[O:21])[CH3:20]
Reactant: COC(=O)CN=[N+]=[N-]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)nn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (408 mg, 1.298 mmol) in N,N-dimethylformamide (DMF) (8 mL) and methanol (0.9 mL) were successively added methyl azidoacetate (299 mg, 2.60 mmol) and copper(I) iodide (12.36 mg, 0.065 mmol). The resulting mixture was stirred at 100° C. under microwave irradiation for 2 h then cooled to room temperature and partitioned between brine and AcOEt. The layers were separated. The aqueous phase was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over a Na2SO4 cartridge and concentrated in vacuo. Purification of the residue on SP4 using a 25 G silica cartridge (gradient: 2 to 10% MeOH in DCM) gave methyl {4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-1,2,3-triazol-1-yl}acetate (468 mg, 1.046 mmol, 96%) as a viscous yellow oil.