Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2].CC[N:23](C(C)C)[CH:24]([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:20])[NH:23][CH:24]([CH3:26])[CH3:25])=[CH:16][CH:17]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(Cc2ccc(C(=O)O)cc2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)N
Product: CCOC(=O)c1cnn(Cc2ccc(C(=O)NC(C)C)cc2)c1
Temperature: 23 °C

Procedure:
To a solution of 1-(4-carboxy-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (50 mg, 0.153 mmol) in DCM (1 ml) were added DIPEA (40.1 μl, 0.230 mmol), HBTU (63.9 mg, 0.168 mmol) and isopropylamine (13 μl, 0.153 mmol). Reaction mixture was stirred over a weekend at 23° C. The solvent was evaporated, and the residual oil was dissolved in ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and brine. Organic layer was dried (sodium sulfate), filtered and evaporated to afford the title compound. HPLC (method G) Rt=1.761 min; UPLC (method F) Rt=0.79 min, MS [M+H]+316.3.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:5]([C:7]([NH2:9])=O)[N:6]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:5]([C:7]#[N:9])[N:6]=1
Reactant: Cc1nc(C(N)=O)c(Nc2ccccc2[N+](=O)[O-])s1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
Combine 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylic acid amide (60 g, 215 mmol) and toluene and add POCl3 (40 mL, 430 mmol) and reflux the reaction mixture. After 2.5 h cool to 0° C. Add saturated NaHCO3 solution to quench the extra POCl3 (Caution!!) until the aqueous was around pH 8. Add ethyl acetate (2×2 L) to extract the product. Combined organic layer and wash with brine (2×1 L), dry over MgSO4, and evaporate to give a reddish solid which triturated with 25% ethyl acetate in hexane to give a reddish solid (36 g). Evaporate the filtrate to half volume to give second batch of compound (3.2 g). Total yield (39.2 g, 70%): mass spectrum (m/e): 261 (M+1); 1HNMR(300 MHz, DMSO, ppm): 2.70 (s, 1H), 7.02 (t, 1H), 7.22 (d, 1H), 7.58 (t, 1H), 8.25 (d, 1H), 9.78 (s, 1H). ). 13CNMR(75MHz, DMSO, ppm): 20.4, 113.1, 116.2, 118.7, 121.2 127.0, 134.9, 136.6, 140.0, 148.6, 161.5. Formula: C11H8N4O2S
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[C:20]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:24]1)(=[O:22])[CH3:21]>>[C:20]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:34])=[CH:36][CH:37]=2)[CH2:24]1)(=[O:22])[CH3:21]
Reactant: CC(=O)N1CCCC(c2ccc(C(=O)O)cc2)C1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: CC(=O)N1CCCC(c2ccc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2)C1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(1-acetyl-piperidin-3-yl)-benzoic acid. MS: 489.3 (M+H).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([O:21]C)=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 85 °C

Procedure:
Methyl 7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 13-cyclohexyl-3-methoxy-6-[[[2-(dimethylamino)-2-oxoethyl]methylamino]carbonyl]- (117 mg, 0.21 mmol) was dissolved into THF/MeOH (1:1, 2 mL) and 1M NaOH (aq.) (0.5 mL, 0.5 mmol). The reaction mixture was heated in a sealed tube with microwave irradiation at 85° C. for 20 min. The reaction was cooled, neutralized with 1M HCl (aq.) (0.5 mL, 0.5 mmol) and concentrated to remove organic solvents. The residue was slurried with H2O and the solids were collected by filtration, flushed with H2O, and purified by preparative HPLC to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[[[2-(dimethylamino)-2-oxoethyl]methylamino]carbonyl]- (71 mg, 0.13 mmol, 63%) as a yellow solid. Mixture of amide rotamers: 1HNMR (500 MHz, CD3OD) δ 8.24 (br s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.18-6.88 (m, 2H), 7.14 (dd, J=8.4, 2.2 Hz, 1H), 5.14 (br s, 1H), 4.49-4.12 (m, 2H), 3.97-3.88 (m, 1H), 3.93 (s, 3H), 3.15-2.83 (m, 7H), 2.56 (s, 1.5H), 2.42 (s, 1.5H), 2.23-1.73 (m, 6H), 1.59-1.17 (m, 4H). LCMS: m/e 530 (M+H)+, ret time 1.40 min, column A, 2 minute gradient.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].[CH2:28]([NH2:33])[CH2:29][CH2:30][CH2:31][CH3:32].[C-]#N.[Na+]>>[CH2:28]([NH:33][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4])[CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: COC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CCCCCN
Agent: [C-]#N
Agent: [Na+]
Product: CCCCCNC(=O)c1cnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]thiazole-5-carboxylic acid methyl ester (0.317 g, 0.79 mmol), amylamine (2.0 mL) and NaCN (0.078 g, 1.59 mmol) was stirred at room temperature overnight. The title compound was obtained as a white powder after purification by column chromatography (0.207 g, 8.5% in 2 steps). m.p. 92-94° C. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.5 Hz, 1H), 7.63-7.51 (m, 2H), 7.39 (s, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.14-7.05 (m, 1H), 4.05-3.82 (m, 2H), 3.65-3.51 (m, 2H), 3.42-3.29 (m, 6H), 1.60-1.46 (m, 2H), 1.33-1.24 (m, 4H), 0.87 (t, J=4.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 170.1, 167.5, 161.2, 146.6, 134.2, 132.3, 129.5, 127.2, 126.8, 125.4, 121.7, 112.5, 48.1, 48.0, 40.8, 39.2, 29.4, 29.1, 22.3, 14.0. MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][CH:10]=O.[Cl-].[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N12CCCN=C1CCCCC2>>[CH2:13]([O:20][C:21]1[CH:46]=[CH:45][CH:44]=[CH:43][C:22]=1[CH:23]=[CH:10][CH:9]=[CH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC=Cc1ccccc1Cl
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Product: Clc1ccccc1C=CC=Cc1ccccc1OCc1ccccc1
Yield: 90 %

Procedure:
Then, following a procedure similar to that described in the first part of Preparation 3, the whole of this 3-(2-chlorophenyl)-2-propenal was reacted with 7.97 g of 2-benzyloxybenzyltriphenylphosphonium chloride (prepared as described in Preparation 1) and 3.35 g of 1,8-diazabicyclo[5,4,0]undec-7-ene. The resulting crude product was purified as described in the first part of Preparation 3, to give 4.57 g (yield 90%) of 1-(2-benzyloxyphenyl)-4-(2-chlorophenyl)butadiene as an oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].O.[NH2:35][NH2:36]>O1CCOCC1>[C:1]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[F:33])=[N:6][C:7]([S:11][CH3:12])=[N:8][C:9]=1[NH:35][NH2:36])(=[O:3])[NH2:2]
Reactant: CSc1nc(Cl)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(NN)c(C(N)=O)c(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2F)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of Example 28C (497 mg, 1 mmol) in 1,4-dioxane (10 mL) was added hydrazine hydrate (0.3 mL). After stirring at ambient temperature for about 4 hours, the mixture was concentrated. The residue was washed with hexane and dried under vacuum to give the title compound, which was used in the next step without further purification. MS: 493 (M+H+).
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][CH2:7][CH2:8][CH:9]=[CH:10][Sn](CCCC)(CCCC)CCCC)([CH3:4])([CH3:3])[CH3:2].OS(C(F)(F)F)(=O)=O.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)#[N:35]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([Si:5]([CH3:24])([CH3:25])[O:6][CH2:7][CH2:8][CH:9]=[CH:10][C:45]1[CH:44]=[CH:43][C:42]([C:39]2[CH:38]=[CH:37][C:36]([C:34]#[N:35])=[CH:41][CH:40]=2)=[CH:47][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(-c2ccccc2)cc1
Reactant: CCCC[Sn](C=CCCO[Si](C)(C)C(C)(C)C)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC=Cc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of Example 31B (4.95 g, 10.4 mmol), 4′-cyanobiphenyl triflate (3.1 g, 9.48 mmol, prepared from 4′-hydroxybiphenyl-4-carbonitrile by standard methods), and Pd(PPh3)2Cl2 (0.332 g, 0.47 mmol) in DMF (20 mL) was stirred at 80° C. overnight. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (97.5:2.5 hexane/ethyl acetate) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ 0.07 (s, 6H), 0.91 (s, 9H), 2.46 (q, J=6 Hz, 2H), 3.75 (t, J=6 Hz, 2H), 6.32 (d, J=16 Hz, 1H), 6.48 (d, J=16 Hz, 1H), 7.44 (d, J=9 Hz, 2H), 7.54 (d, J=9 Hz, 2H), 7.65-7.74 (m, 4H). MS (DCl—NH3) m/z 364 (M+H)+, m/z 359 (M+NH4)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:42](=[O:43])[C@H:40]([CH3:41])[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 67.4 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-L-alanylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (310 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (300 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine (300 mg) according to a similar manner to that of Example 5, mp. 154°-156° C.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:28]1[N:33]=[C:32]2[C:34]([C:56]([NH:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[CH:35][N:36]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]2=[N:30][CH:29]=1>CN(C=O)C.O.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.[Cu](I)I>[C:59]([NH:58][C:56]([C:34]1[C:32]2=[N:33][C:28]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH:2]([F:1])[F:26])[CH:5]=4)[NH:9][N:8]=3)=[CH:29][N:30]=[C:31]2[N:36]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Yield: 56.8 %

Procedure:
A mixture of 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (250 mg, 0.57 mmol), 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (280 mg, 0.58 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), copper iodide (26 mg, 1.36 mmol) in 10 mL of dry DMF was heated to 90° C. for 3 hours under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, product extracted with ethyl acetate (3×20 mL), organics combined dried with sodium sulfate, filtered and concentrated to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (208 mg, crude). LCMS: (M+H)+=643.
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20](O)=[O:21])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br.[NH2:26][CH2:27][CH:28]1[CH2:37][CH2:36][C:31]2[N:32]=[C:33]([NH2:35])[S:34][C:30]=2[CH2:29]1>>[NH2:35][C:33]1[S:34][C:30]2[CH2:29][CH:28]([CH2:27][NH:26][C:20](=[O:21])[CH2:19][N:14]3[C:15]([CH3:18])=[CH:16][CH:17]=[C:12]([NH:11][S:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)(=[O:10])=[O:9])[C:13]3=[O:23])[CH2:37][CH2:36][C:31]=2[N:32]=1
Reactant: NCC1CCc2nc(N)sc2C1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Agent: Br
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NCC1CCc2nc(N)sc2C1

Procedure:
The title compound was prepared from 2-[3-[(benzylsulfonyl)amino]-6 -methyl-2-oxo-1(2H)-pyridinyl]acetic acid and 6-(aminomethyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2 -amine dihydrobromide using the procedure of EXAMPLE 1 (STEP 6), and was obtained as a pale solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:25]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)cc2C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
2-(2,4-Dimethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (414 mg, 1.23 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.42 g, 24.7 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with concentrated HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (275) as white solid (350 mg, 92%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O>[CH2:21]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCI
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a mixture of 15 g (0.105 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol) of K2CO3, and 100 ml of acetonitrile is added dropwise 18.92 ml (0.105 mol) of iodooctane. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture was diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is triturated with ether and filtered. The filtrate is concentrated in vacuo to yield 24.04 g (90%) of title compound as a clear oil: IR (neat) 2925 and 1094 cm-1 ; NMR (CDCl3) δ3.97 (s, 4H), 2.56 (br, 4H), 2.38 (m, 2H), 1.78 (m, 4H), 1.51 (br, 2H), 1.28 (s, 10H), 0.89 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)#[N:2].[OH:40]O.[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C(N)=O)cc34)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{N-[3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)phenyl]carbamoyl}piperidinecarboxylate in 3 mL of ethanol, was added 3 mL of 30% commercially available H2O2 solution followed by 0.280 mL of 6.0 N aqueous NaOH solution. Within 30 min, the formation of an abundant white precipitate was observed. The mixture was acidified using a 6.0 N aqueous solution of HCl. Upon addition of water (20 mL), the formation of a precipitate was observed. The solid was collected by filtration, washed with small portions of water and dried in a vacuum oven overnight. The desired product was isolated as a pure white solid (0.277 g, 40% over 2 steps): ES-MS (m/z) 548 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>ClCCl>[CH3:12][S:13]([O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(F)cc1

Procedure:
As for Example 56, 12.5 g of 2-(p-fluorophenoxy) ethanol is reacted with 7 ml of methanesulfonyl chloride in 100 ml of dichloromethane in the presence of 23 ml of triethylamine. The product (18 g) is obtained as a colorless liquid.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:6]([Sn](C)(C)C)=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1>ClCCl>[Br:1][C:10]1[CH:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[N:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: BrBr
Reactant: COc1ccc(C(F)(F)F)nc1[Sn](C)(C)C
Solvent: ClCCl
Product: COc1cnc(C(F)(F)F)cc1Br

Procedure:
Prepared from bromine (0.21 ml, 4 mmol) and a solution of 3-methoxy-6-trifluoromethyl-2-trimethylstannylpyridine (0.7 g, 2.0 mmol) in dichloromethane (10 ml) according to the method of Description 42 to afford 4-bromo-3-methoxy-6-trifluoromethylpyridine as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([NH:21][C:22](=O)[CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([NH:21][CH2:22][CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COc1ccc(CCC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: CCCCC
Product: COc1ccc(CCCNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 99 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-3-(4-methoxyphenyl)propionamide, the title compound was synthesized according to Example 2b. Yield: 99%. Melting point: 62-65° C. (Pentane)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH:37]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:33]4[CH:34]=[N:35][N:36]([CH2:38][CH2:39][N:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)[CH:37]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cnn(CCN4CCOCC4)c3)ccc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine were reacted to give 269. MS: (ESI+)=512.2
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=3)[C:13](=[O:23])[O:12][N:11]=2)=[N:7][O:8][N:9]=1
Reactant: [N-]=[N+]=NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
3-[4-(Azidomethyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (225 mg, 0.66 mmol) was dissolved in anhydrous THF (5.6 mL) and water (5.6 mL). The reaction was cooled to 0° C. followed by addition of triphenylphosphine (192 mg, 0.73 mmol). The reaction was allowed to warm to rt and was stirred overnight. The reaction was stripped to dryness, azeotroped with toluene and redissolved in MeOH. The crude residue was purified by preparative LCMS to yield the desired product (200 mg, 96%). MF=C11H7ClFN5O3; LCMS calculated for C11H8ClFN5O3(M+H)+: m/z=312.030.