Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([NH:11][CH:12]([CH3:14])[CH3:13])=[N:4][C:5]([S:9][CH3:10])=[N:6][C:7]=1[CH3:8].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[CH:12]([NH:11][C:3]1[C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH3:8])[N:6]=[C:5]([S:9][CH3:10])[N:4]=1)([CH3:14])[CH3:13]
Reactant: CSc1nc(C)c(I)c(NC(C)C)n1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(SC)nc1NC(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-Iodo-N-isopropyl-6-methyl-2-(methylthio)pyrimidin-4-amine (8.1 g, 26.2 mmol), ethyl acrylate (5.24 g, 52.4 mmol), triethylamine (10.6 g, 105 mmol), palladium (II) acetate (1.17 g, 5.23 mmol), and tri-o-tolyl phosphine (1.59 g, 5.23 mmol) were added in that order to 10.8 mL of DMA in a pressure tube and sealed. The reaction mixture was heated to 100° C. and allowed to stir overnight. The reaction was quenched by filtration through a short silica plug washing with ACN. The solvent was evaporated and diluted with ethyl acetate then extracted with 10% aqueous LiCl, followed by water and brine. NOTE: Extraction is necessary to remove all DMA giving resolution in chromatography. The sample was purified by silica gel column chromatography using 20% ethyl acetate/hexane as eluent. Desired fractions were combined and reduced to afford 2.5 g (34% yield) of ethyl (2E)-3-[4-(isopropylamino)-6-methyl-2-(methylthio)pyrimidin-5-yl]acrylate as a yellow/orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.C(N(CC)CC)C.[Cl:38][C:39]1[C:44]([NH:45][C:46]2[N:51]=[C:50]([N:52]([CH:62]3[CH2:64][CH2:63]3)[CH2:53][C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)[C:49]3=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]3[N:47]=2)=[CH:43][C:42]([C:70]#[N:71])=[CH:41][C:40]=1[N:72]1[CH2:77][CH2:76][C@@H:75]([NH:78][C:79](=[O:82])[O:80][CH3:81])[C@H:74](O)[CH2:73]1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][C@@H:76]1[C@@H:75]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH2:74][CH2:73][N:72]([C:40]2[CH:41]=[C:42]([C:70]#[N:71])[CH:43]=[C:44]([NH:45][C:46]3[N:51]=[C:50]([N:52]([CH:62]4[CH2:64][CH2:63]4)[CH2:53][C:54]4[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=4)[C:49]4=[N:65][CH:66]=[C:67]([C:68]#[N:69])[N:48]4[N:47]=3)[C:39]=2[Cl:38])[CH2:77]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCN(c2cc(C#N)cc(Nc3nc(N(Cc4ccc(OC)cc4)C4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@@H]1OC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (30.4 mg, 0.140 mmol), Tetramethylfluoroformamidinium hexafluorophosphate (37.0 mg, 0.140 mmol) and triethyl amine (0.039 mL, 0.280 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 h. (+/−)-methyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (Example 171, 18 mg, 0.028 mmol) and DMAP (0.342 mg, 2.80 mol) were added and the reaction solution was stirred at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-30% ethyl acetate/dichloromethane). (+/−)-(R)-(3S,4S)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-4-((methoxycarbonyl)amino)piperidin-3-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (23 mg) was obtained as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[H-].[Na+].[CH2:8]([NH:20][C:21](=[O:41])[C:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[C:25]([O:36][CH2:37][CH2:38]Br)=[C:24]([Br:40])[CH:23]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].N[C@H](C(O)=O)[C@@H](C)O>C1COCC1.CCOC(C)=O.CS(C)=O>[CH2:8]([NH:20][C:21]([C:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)[C:25]([O:36][CH2:37][CH2:38][N:1]2[CH:5]=[N:4][N:3]=[N:2]2)=[C:24]([Br:40])[CH:23]=1)=[O:41])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCBr)c(-c2cccc(OC)c2)c1
Reactant: c1nnn[nH]1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCNC(=O)c1cc(Br)c(OCCn2cnnn2)c(-c2cccc(OC)c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24.7 %

Procedure:
To a solution of 1H-tetrazole (28 mg, 0.4 mmol) in 1 mL anhydrous THF at 0° C. was added NaH (10 mg, 0.421 mmol). The reaction mixture was stirred for 10 min at 0° C. after which point a solution of N-dodecyl-3-bromo-4-(2-bromoethoxy)-5-(3-methoxyphenyl)benzamide (160 mg, 0.276 mmol) in 2.5 mL anhydrous THF was added. The reaction mixture was stirred at 0° C. for 10 min then allowed to warm up to room temperature for one-half hour. Then 700 μL of DMSO was added and the reaction was then heated at 65° C. overnight. Thr reaction was quenched and diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and the solvent removed in vacuo to give a brown-yellow oil. The crude material was subjected to flash column chromatography (25% EtOAc: 75% Hexanes to 40% EtOAc: 60% Hexanes to 50% EtOAc: 50% Hexanes) to yield 40 mg, 25% of a white solid. mp 100–1° C.; 1H NMR (DMSO-d6) δ 0.88 (t, J=6.80 Hz, 3H); 1.25–1.37 (m, 18H); 1.60 (quintet, J=7.14 Hz, 2H); 3.43 (q, J=7.14 Hz, 2H); 3.84 (s, 3H); 3.96 (t, J=4.86 Hz, 2H); 4.57 (t, J=4.86 Hz, 2H); 6.01 (t, J=5.00 Hz, 1H); 6.93–6.95 (m, 3H); 7.27–7.32 (m, 1H); 7.64 (d, J=2.20 Hz, 1H); 7.94 (d, J=1.98 Hz, 1H); 8.68 (s, 1H); IR 3330, 2900, 2840, 1625, 1600, 1520, 1460, 1310, 1300, 1235, 1175, and 1030 cm−1; mass spectrum [(+)ESI] m/z 586/588 [M+H]+; Anal Calcd. For C29H40BrN5O3: C, 59.38; H, 6.87; N, 11.94. Found: C, 59.46; H, 6.68; N, 11.77.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[C:18](=[O:23])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.[C:25]([Cu])#[N:26]>>[CH:20]([N:19]1[C:18](=[O:23])[NH:17][N:16]=[C:15]1[C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:25]#[N:26])=[CH:24][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)([CH3:22])[CH3:21]
Reactant: N#C[Cu]
Reactant: CC(C)n1c(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n[nH]c1=O
Product: CC(C)n1c(-c2cc3c(s2)-c2ccc(C#N)cc2OCC3)n[nH]c1=O

Procedure:
Following the procedure of Example 53, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one and CuCN were reacted to give 259. MS: (ESI+) 353.1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11].[CH3:12][O:13][C:14]([N:16]=[C:17]=[S:18])=[O:15]>CC(C)=O>[CH3:12][O:13][C:14]([NH:16][C:17](=[S:18])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[NH:11][C:17]([NH:16][C:14]([O:13][CH3:12])=[O:15])=[S:18])=[O:15]
Reactant: COC(=O)N=C=S
Reactant: N#CSc1ccc(N)c(N)c1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(SC#N)cc1NC(=S)NC(=O)OC

Procedure:
2.6 G. 1,2-diamino-4-thiocyanatobenzene in 48 ml. acetone is treated overnight with 8 g. methoxy carbonyl isothiocyanate at room temperature. The solution is concentrated and the residue triturated with methanol and recrystallized from methanol-chloroform, yielding pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-thiocyanatobenzene.
Reaction SMILES: C1(CCCC[OH:11])C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1.[CH2:23]1[CH2:30][CH:29]2[N:31]([O])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH2:23]1[CH:30]2[CH:29]3[NH+:31]([O-:11])[CH:25]([CH2:24]2)[CH2:26][CH:27]1[CH2:28]3
Reactant: [O]N1C2CCCC1CCC2
Reactant: OCCCCc1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Product: [O-][NH+]1C2CC3CC(C2)C1C3

Procedure:
In the oxidation of 4-phenylbutanol (entry 1), which is a primary alcohol, when the catalyst amount was 1 mol %, all the catalyst compounds gave the objective substance in a high yield, but when the catalyst amount was reduced, marked differences was observed in the catalytic activity. Specifically, in the case of using TEMPO, when the catalyst amount was reduced to 0.01 mol %, marked decrease of the yield was observed, and in the case of ABNO, when the catalyst amount was reduced to 0.003 mol %, the yield decreased to about 60%. In contrast, Nor-AZADO gave the objective substance in a high yield even when the catalyst amount was reduced to 0.003 mol %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C@H:20]([C:21]([OH:23])=O)[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=3)[CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(Cl)CCl>CN(C=O)C.O>[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:21]([C@@H:20]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[CH:17]=3)[CH2:12][N:11]2[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:10])=[O:23])=[CH:36][CH:35]=1
Reactant: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)O)C2
Reactant: CN1CCN=C1c1ccc(N)cc1
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(C(=O)Nc1ccc(Cl)cc1)[C@H](C(=O)Nc1ccc(C3=NCCN3C)cc1)C2
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of (3S)-2N-(4-chlorophenylaminocarbonyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (25 mg, 0.064 mmol) and 4-(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)-phenylamine (23 mg, 0.13 mmol) in DMF (2 mL) and H2O (0.5 mL) at room temperature, EDC (49 mg, 0.26 mmol) was added. The mixture was stirred at room for 2 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a white powder (20 mg). MS 548.2 and 550.2 (M+H, Cl pattern).
Reaction SMILES: O[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.COCCN(S(F)(F)[F:44])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[F:44][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@@H]1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 0.15 g, 0.35 mmol) was dissolved in dichloromethane (5 mL), cooled to 0° C. and treated with bis(2-methoxyethyl)aminosulfur trifluoride (0.15 mL, 0.70 mmol, 2 equiv). The mixture was stirred at 0° C. for 30 minutes and then treated with additional bis(2-methoxyethyl)aminosulfur trifluoride (75 μL, 0.35 mmol, 1 equiv). After stirring for an additional 30 minutes, the mixture was treated with sodium bicarbonate (5 mL, aqueous saturated) and stirred vigorously for 15 minutes. The mixture was poured into sodium bicarbonate (75 mL, aqueous saturated) and extracted with dichloromethane (2×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 85:15; ethyl acetate:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.39 (1H, s), 8.38-8.35 (1H, m), 7.89 (1H, d, J=2.5 Hz), 7.71 (1H, d, J=1.8 Hz), 7.69 (2H, d, J=8.6 Hz), 7.47-7.42 (2H, m), 7.40-7.36 (1H, m), 7.28-7.26 (2H, m), 6.46 (1H, dd, J=2.4, 1.8 Hz), 5.45 (2H, s), 5.03 (1H, dtd, J=49.9, 10.6, 5.0 Hz), 4.61-4.52 (1H, m), 2.34-2.27 (1H, m), 2.06-1.98 (2H, m), 1.91-1.80 (2H, m), 1.74-1.59 (1H, m), 1.52-1.43 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 442.2051 [(M+H)+; calculated for C26H25FN5O: 442.2038].
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:41]=[CH:40][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH:68]2[CH2:70][O:69]2)=[CH:62][CH:61]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH:35]1([O:34][C:28]2[CH:27]=[C:26]([CH:23]3[CH2:22][CH2:21][N:20]([C:18]([N:15]4[CH2:14][CH2:13][CH:12]([NH:11][C:10]5[CH:40]=[CH:41][C:7]([CH2:6][CH2:5][NH:4][CH2:70][C@H:68]([OH:69])[CH2:67][O:66][C:63]6[CH:64]=[CH:65][C:60]([OH:59])=[CH:61][CH:62]=6)=[CH:8][CH:9]=5)[CH2:17][CH2:16]4)=[O:19])[CH2:25][CH2:24]3)[CH:31]=[CH:30][C:29]=2[O:32][CH3:33])[CH2:36][CH2:37][CH2:38][CH2:39]1
Reactant: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCN)cc4)CC3)CC2)cc1OC1CCCC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2CCN(C(=O)N3CCC(Nc4ccc(CCNC[C@H](O)COc5ccc(O)cc5)cc4)CC3)CC2)cc1OC1CCCC1
Yield: 20.6 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}{4-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-piperidinyl}methanone formate (0.50 g, 0.88 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.350 g, 0.88 mmol) according to Procedure G to yield (eluant: 20:1 chloroform-methanol) the title compound (0.168 g, 0.181 mmol)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:11].O1CCC[CH2:20]1>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH2:20][O:18]1
Reactant: CC(C(=O)c1ccc(F)cc1F)c1cccnc1
Reactant: C1CCOC1
Solvent: O
Product: CC(c1cccnc1)C1(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of dimethylsulphoxonium methylide (36.5 ml of a 0.6M solution in tetrahydrofuran) was added dropwise to a stirred solution of the product of part (ii) (4.36 g) in tetrahydrofuran (35 ml) at -20° . The solution was allowed to warm to room temperature and stirring was continued for 18 hours and then diluted with water. The mixture was extracted with ethyl acetate and the combined extracts were dried (Na2SO4). Evaporation of the solvent gave the title compound as an oil (4.50 g) which was used directly in the next stage.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](=[CH2:11])[CH3:10]>>[C:9]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:9]([CH3:11])([CH3:10])[CH3:8])[C:1]=1[OH:7])([CH3:10])([CH3:8])[CH3:11]
Reactant: Oc1ccccc1
Reactant: C=C(C)C
Product: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 100 %

Procedure:
Phenol and the above-mentioned catalyst are charged into a reactor; the mixture is heated to 100°-110° C. and isobutylene is passed thereinto for 8 hours. The resulting alkylate is subjected to a vacuum-rectification. After recrystallization of the product from aliphatic hydrocarbons, a 100% pure 2,6-di-tertbutylphenol is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1>O>[Cl:11][C:4]1[N:3]=[C:2]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: c1ccc2c(c1)CCNC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1N1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
2,6-Dichloro-3-nitropyridine (10 g, 51.8 mmol) and sodium carbonate (8.8 g, 82.9 mmol) were added to anhydrous N,N-dimethylformamide (250 ml). 1,2,3,4-tetrahydroisoquinoline (7.14 ml, 82.9 mmol) was added at 0° C. to the reaction mixture, which was then stirred for 2 hours at 0° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 10 g of the titled compound as yellow solid. (Yield: 81%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[Cl:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[Cl:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(F)c3Cl)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-chloro-3-fluorophenyl)boronic acid gave 337. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.20-8.12 (m, 1H), 7.84 (s, 1H), 7.52 (s, 2H), 7.50-7.39 (m, 2H), 4.82 (dd, J=10.7, 3.6 Hz, 1H), 4.53-4.36 (m, 1H), 4.33-4.20 (m, 1H), 4.14-3.98 (m, 1H), 3.76 (s, 3H), 2.09-2.01 (m, 1H), 1.88-1.66 (m, 4H). LCMS (ES+) m/z 483 (M+1).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([OH:13])[CH:6]=1.C[O:16][C:17](=O)[CH2:18][C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.N1CCCCC1>C(#N)C.C1C=CC=CC=1>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[C:18]1[C:17](=[O:16])[O:13][C:7]2[C:8]([CH:9]=1)=[CH:11][CH:12]=[C:5]([N:4]([CH2:3][CH2:2][F:1])[CH3:14])[CH:6]=2
Reactant: COC(=O)Cc1nc2ccccc2s1
Reactant: CN(CCF)c1ccc(C=O)c(O)c1
Solvent: CC#N
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CN(CCF)c1ccc2cc(-c3nc4ccccc4s3)c(=O)oc2c1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
130 mg (ca. 0.65 mmol) crude 4-[(2-Fluoro-ethyl)-methyl-amino]-2-hydroxy-benzaldehyde and 202 mg (1.5 eq.) benzothiazol-2-yl-acetic acid methyl ester are dissolved in 3 mL acetonitrile and 6 mL benzene, treated with 0.14 mL (2 eq.) piperidine and heated to reflux for 45 minutes. After cooling to room temperature, the crude product is extracted with AcOEt/isopropanol 9:1 and saline, dried over sodium sulfate and evaporated. The crude product is dissolved in 20 mL methanol, and slowly concentrated down to 10 mL at 50° C. The orange crystals are filtered and dried under high vacuum to yield 110 mg (48%) desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].C(O)(=O)C>C1C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:11]([C:12]([CH3:14])=[O:13])[C:10]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccccc1Cl
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccccc1Cl)C(C)=O
Yield: 98.1 %

Procedure:
A mixture of 25.0 g of 2-chlorobenzaldehyde, 23.1 g of ethyl acetoacetate, 2.1 g of acetic acid and 0.6 g of piperidine in 100 cc of benzene was heated under reflux for 8 hours and removed water by a Dean-Stark trap. After cooling, to the reaction mixture was added ethylacetate and water. The organic layer was further washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the crude product thus obtained was purified by a silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to obtain 44.0 g of compound A. Yield: 97.9%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([NH2:12])[CH:9]([NH2:11])[CH3:10])=[CH:4][CH:3]=1.CO[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#N)[CH:25]=1)=[NH:23].C(Cl)(Cl)Cl>CO>[C:22]([C:24]1[CH:25]=[C:26]([C:30]2[NH:11][CH:9]([CH3:10])[C:8]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:12]=2)[CH:27]=[CH:28][CH:29]=1)#[N:23]
Reactant: CC(N)C(N)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=N)c1cccc(C#N)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC1NC(c2cccc(C#N)c2)=NC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14 %

Procedure:
1,1-bis(4-fluorophenyl)-1,2-propanediamine(50 mg) was dissolved in methanol(1 mL), and to the solution was added 3-cyanobenzeneimidic acid methyl ester (75 mg). The mixture was stirred at room temperature for 24 hrs. After chloroform (5 ml) was added to the reaction mixture, insolubles were removed by filtration. After concentrating the filtrate in vacuo, the obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=3:1→1:1) to give the objective compound (10 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=O.[OH:20][C:21]1[N:25]([CH3:26])[N:24]=[C:23]([CH:27]2[CH2:29][CH2:28]2)[CH:22]=1.[CH3:30]CN=C=NCCCN(C)C.CCN(CC)CC.[Si](C#N)(C)(C)C.[C-]#N.[K+]>CC#N>[CH:27]1([C:23]2[C:22]([C:9]([C:8]3[CH:12]=[CH:13][C:14]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:6]([N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH3:30])[C:7]=3[CH3:19])=[O:11])=[C:21]([OH:20])[N:25]([CH3:26])[N:24]=2)[CH2:29][CH2:28]1
Reactant: Cn1nc(C2CC2)cc1O
Reactant: COCCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Reactant: CCN=C=NCCCN(C)C
Agent: C[Si](C)(C)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCCN(C)c1c(S(C)(=O)=O)ccc(C(=O)c2c(C3CC3)nn(C)c2O)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under nitrogen, 0.59 g of crude 3-[(2-methoxyethyl)amino]-2-methyl-4-(methylsulfonyl)benzoic acid was dissolved in 30 ml of CH3CN, and 0.35 g (3 mmol) of 5-hydroxy-3-cyclopropyl-1-methylpyrazole and 0.45 g (2 mmol) of EDAC were then added. The mixture was stirred at RT for one day. 0.36 g (4 mmol) of NEt3, 0.08 g (1 mmol) of Me3SiCN and a spatula tip of KCN were then added, and the mixture was stirred at RT for two days. The mixture was then concentrated, and the residue was taken up in 100 ml of CH2Cl2 and washed with 10% strength H2SO4. The organic phase was dried over MgSO4, concentrated and the residue was purified chromatographically (SiO2, EA/n-heptane=1:1+5% acetic acid). This gave a brown oil.