Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[O:6]=[S:7]1(=[O:32])[CH:12]=[CH:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25]C(=O)C(F)F)[O:21][C:20]3=[O:31])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>N1C=CC=CC=1.ClCCl>[O:32]=[S:7]1(=[O:6])[CH:8]=[CH:9][CH:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:2](=[O:3])[O:4][CH3:5])[O:21][C:20]3=[O:31])=[CH:17][CH:18]=2)[CH2:11][CH2:12]1
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Methyl chloroformate (0.072 mL, 0.925 mmol) is added dropwise at 0° C. to to the crude amine hydrochloride prepared in Step 1 of Example 15 (0.316 g, 0.881 mmol) in a mixture of pyridine (4 mL) and dichloromethane (4 mL). The mixture is allowed to warm to room temperature, stirred for 1 hour, and then evaporated to dryness. The residue is purified by PTLC (10% methanol/dichloromethane) to give white solid (0.26 g, 78%). M.p. 196–7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](Cl)=[N:5][OH:6].[CH3:12][O:13][C:14](=[O:19])[CH2:15][C:16]([CH3:18])=O.C[O-].[Na+]>CO>[CH3:12][O:13][C:14]([C:15]1[C:4]([C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:5][O:6][C:16]=1[CH3:18])=[O:19]
Reactant: ON=C(Cl)c1ccccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2Cl)noc1C
Yield: 59.6 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), 2-chloro-N-hydroxybenzimidoylchloride (8.0 g, 42.10 mmol), methylacetoacetate (9.78 g, 84.20 mmol) and sodium methoxide (6.83 g, 126.30 mmol), a white solid required compound (6.32 g, 25.11 mmol, 60%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[N:14]([CH2:18][CH3:19])[N:15]=[CH:16][CH:17]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[N:14]([CH2:18][CH3:19])[N:15]=[CH:16][CH:17]=3)=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCn1nccc1C(=COC)c1cc(Br)cnc1N
Agent: Cl
Solvent: CCO
Product: CCn1nccc1-c1c[nH]c2ncc(Br)cc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
5-Bromo-3-[1-(2-ethyl-2H-pyrazol-3-yl)-2-methoxy-vinyl]-pyridin-2-ylamine (602 mg, 1.86 mmol), ethyl alcohol (30 ml), and concentration hydrochloric acid (30 ml) were combined and stirred at 100° C. for 18 hours. The reaction was quenched with sodium bicarbonate solution and the product was filtered off. The filtered product was dried under high vacuum to give 320 mg (59%) of 5-bromo-3-(2-ethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine. MS: m/z 291.3+293.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (63.5, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28](O)=[O:29])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:56][CH2:57][CH2:58][NH2:59].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:56][CH2:57][CH2:58][NH:59][C:28]([C:14]1[N:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=2)[CH:16]=[C:12]([NH:11][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:31])=[O:10])[N:13]=1)=[O:29]
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Reactant: NCCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCCl)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
90.6 mg (0.2 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 500 μl of DMF, and 36.65 mg (0.3 mmol) of DMAP and 114 mg (0.3 mmol) of HATU are added. After stirring at RT for 5 minutes, a solution of 46.4 mg (0.4 mmol) of 1-chloro-2-aminoethane and 25.8 mg (0.2 mmol) of N,N-diisopropylethylamine in 500 μl of DMF is added dropwise. The reaction mixture is stirred at RT for 6 h, then filtered and purified by preparative HPLC (method 9). The product-containing fractions are evaporated in vacuo.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=O)[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:4]2[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[N:2]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)CCCCN(CC)CC
Agent: Cl
Product: CCOC(=O)c1c(CCCCN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 49, 2-amino-4,5,3',4'-tetramethoxybenzophenone hydrochloride was reacted with ethyl 7-(N,N-diethylamino)-3-oxoheptanoate to give ethyl 2-[4-(N,N-diethylamino)butyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 171°-172° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2].[K+].[Br-]>>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][C:6]=1[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccccc2)c(NC(C)=O)c2cc([N+](=O)[O-])ccc21
Agent: [Br-]
Agent: [K+]
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-2-benzoyl-1-(ethoxycarbonyl)-5-nitroindole (step 3). m.p.: 210-212° C. 1H-NMR (CDCl3+CDOD3) δ: 9.14 (1H, d, J=1.8 Hz), 8.19 (1H, dd, J=2.6, 9.2 Hz), 7.84 (1H, d, J=8.8 Hz), 7.4-7.8 (5H, m), 2.20 (3H, s) IR (KBr) ν: 1665, 1620, 1435, 1345, 1265, 1020, 915, 820 cm−1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:13][CH:14]=2)[C:9]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:8]1[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(C(C)C)CC)(C)C.Cl[C:47]1[O:48][C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[O:48]1[C:49]2[CH:55]=[CH:54][CH:53]=[CH:52][C:50]=2[N:51]=[C:47]1[N:19]([CH3:20])[CH2:18][CH2:17][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:5]1[CH:34]=[CH:35][CH:36]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:8]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:9]2[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCNC)ccc2n1Cc1cccc(OC)c1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cc(OCCN(C)c3nc4ccccc4o3)ccc2n1Cc1cccc(OC)c1
Temperature: 120 °C
Yield: 97 %

Procedure:
To a solution of Ethyl 1-(3-methoxybenzyl)-3-(4-methoxyphenyl)-5-[2-(methylamino)ethoxy]-1H-indole-2-carboxylate (Example 156, 100 mg, 0.2028 mmol) in N,N-dimethylformamide (1.5 ml) was added diisopropylethylamine (0.09 ml, 0.5167 mmol, 2.5 eq.) and 2-chlorobenzoxazole (0.03 ml, 0.2636 mmol, 1.3 eq.). The reaction mixture was heated at 120° C. for 4 hr. After cooling the reaction was diluted with saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash column (silica gel, dichloromethane to dichloromethane:methanol 95:5). The desired product was obtained as a light yellow oil in 97% yield (119 mg), MS (M+H)=606.3, Rf=0.69 (dichloromethane/methanol 95:5).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[S:23][N:22]=[C:21]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([NH:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:31])[CH2:26][CH2:25]4)[N:20]=3)[CH2:15][CH2:14]2)=[O:12])=[N:2]1.[ClH:43]>CO.O1CCCC1>[ClH:43].[ClH:43].[NH2:35][CH2:34][CH2:33][NH:32][C:30]([CH:27]1[CH2:26][CH2:25][N:24]([C:21]2[N:20]=[C:19]([N:16]3[CH2:17][CH2:18][N:13]([C:11]([NH:10][C:3]4[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][N:2]=4)=[O:12])[CH2:14][CH2:15]3)[S:23][N:22]=2)[CH2:29][CH2:28]1)=[O:31]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: NCCNC(=O)C1CCN(c2nsc(N3CCN(C(=O)Nc4noc5ccccc45)CC3)n2)CC1
Yield: 91 %

Procedure:
A solution of tert-butyl [2-({[1-(5-{4-[(1,2-benzisoxazol-3-ylamino)carbonyl]piperazin-1-yl}-1,2,4-thiadiazol-3-yl)piperidin-4-yl]carbonyl}amino)ethyl]carbamate (70.0 mg, 0.117 mmol) and a solution of 2 N hydrogen chloride in methanol (10 ml) in tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 61.0 mg (91.0%) of the desired product as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[CH3:17])[C:7]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[S:20][C:6]=2[C:5](=[O:27])[N:4]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1.ClCCl>[Cl:16][C:12]1[C:11]([CH3:17])=[C:10]([CH2:9][N:8]2[C:7]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[S:20][C:6]=3[C:5](=[O:27])[N:4]=[C:3]2[CH2:2][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C1CCNC1
Reactant: Cc1c(Cl)cccc1Cn1c(CBr)nc(=O)c2sc(N3CCOCC3)nc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(Cl)cccc1Cn1c(CN2CCCC2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a 20 mL I-CHEM reaction vial was added a solution of 5-(bromomethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (188 mg, 0.400 mmol) in tetrahydrofuran (THF) (4002 μL). The solution was then treated with pyrrolidine (331 μL, 4.00 mmol) and the resulting reaction mixture was allowed to stir at room temperature and was found to have completely converted to the desired material by LCMS in less than 5 minutes. Reaction mixture was placed under a nitrogen stream and warmed to 50° C. to concentrate the reaction to a residue. The residue was then re-dissolved in dichloromethane (DCM) (750 μL) and injected onto a 10 g SNAP silica cartridge for purification [eluting with a gradient: 0-95% THF (1% methanol (MeOH)) into DCM, over 30 column volumes]. Fractions containing the desired material were pooled and concentrated to afford a residue which was subsequently triturated with ethyl acetate and hexanes to afford pure 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-(1-pyrrolidinylmethyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (38 mg, 0.082 mmol, 20.44% yield). LCMS Theoretical m/z MH+=460.99 Found: 461.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (br. s., 4H) 2.37 (br. s., 4H) 2.41 (s, 3H) 3.46-3.52 (m, 4H) 3.52 (s, 2H) 3.62-3.74 (m, 4H) 5.66 (s, 2H) 6.45 (d, J=7.83 Hz, 1H) 7.11 (t, J=8.21 Hz, 1H) 7.33 (d, J=7.33 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH2:27]([N:34]1[N:43]=[CH:42][C:41]2[C:36](=[CH:37][C:38]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:39][CH:40]=2)[C:35]1=[O:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[N:43]=[CH:42][C:41]2[C:36](=[CH:37][C:38]([N:44]3[CH2:45][CH2:46][N:47]([CH2:23][CH2:22][CH2:21][C:7]4([C:5](=[O:6])[NH:4][CH2:3][C:2]([F:26])([F:25])[F:1])[C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[O:14][C:13]5[C:8]4=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH2:48][CH2:49]3)=[CH:39][CH:40]=2)[C:35]1=[O:50])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1c2cc(N3CCNCC3)ccc2cnn1Cc1ccccc1
Reactant: O=C(NCC(F)(F)F)C1(CCCBr)c2ccccc2Oc2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCN2CCN(c3ccc4cnn(Cc5ccccc5)c(=O)c4c3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Step (c) of Example 92 was repeated, except that the compound prepared in step (b) of Example 114 and the compound prepared in step (e) of Example 137 were used as the starting compounds. Thus, the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)([O-])=O.[NH4+]=S>CCO.O>[N+:10]([C:8]1[CH:9]=[C:4]([NH2:1])[CH:5]=[C:6]([C:13]([F:14])([F:15])[F:16])[CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
To a solution of 3,5-dinitrobenzotrifluoride (10 g, 42 mmols, 1 eq.) in 150 mL of EtOH was added 17.6 mL (258.3 mmols, 6.15 eq.) of ammonium sulfide in water (50% by weight, Aldrich). The reaction was heated to reflux for 16 h during which time it became orange and a yellow precipitate formed. After cooling the volume was reduced to approximately 50 mL. The solid was removed by filtration and the filtrate evaporated to dryness in vacuo. The resulting orange solid was purified by column chromatography eluting with a step gradient of 20-30% EtOAc:hexane to provide the compound as a yellow/orange solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[S:18][CH3:19].I[CH3:21].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:21])[C:9]([C:14]([O:16][CH3:17])=[O:15])=[C:8]2[S:18][CH3:19]
Reactant: CI
Reactant: COC(=O)c1[nH]c2ccc(OC)cc2c1SC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)c2cc(OC)ccc2n1C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (0.30 g, 7.5 mmol) in 3.0 mL of N,N-dimethylformamide is cooled in ice while a solution of methyl 5-methoxy-3-(methylthio)-1H-indole-2-carboxylate (1.3 g, 5.2 mmol) in 10 mL of N,N-dimethylformamide is added dropwise. The mixture is stirred for 45 minutes, then iodomethane (0.50 mL, 1.1 g, 8.0 mmol) is added in one portion. After stirring at room temperature for 8 hours, the mixture is added to 100 g of ice and water. The solid is filtered and washed with 10% methanol-water to yield 1.2 g (88%) of product. A sample purified by flash chromatography (silica gel, 25% hexane in dichloromethane elution) and recrystallized from hexane has mp 89°-91° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.C(O)(=O)C.[N:14]([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[CH:9]=[N:14][NH:8][C:5]2=[CH:6][N:7]=1
Reactant: O=N[O-]
Reactant: Cc1cc(Br)ncc1N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cc2cn[nH]c2cn1
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
To a solution of 6-bromo-4-methylpyridin-3-amine (7.76 g, 0.0415 mol) in acetic acid (412.8 mL, 7.260 mol) was added Sodium nitrite (2.87 g, 0.0416 mol) in 4.0 ml water (Bioorg. Med. Chem. 15 (2007) 2441-2452). The reaction was stirred for 15 min and allowed to stand at room temperature (rt) for 2 days (d). The reaction was concentrated and diluted EtOAc then washed with NaHCO3 and brine. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by chromatography (DCM/MeOH) eluted at 5% MeOH) to give 5-bromo-1H-pyrazolo[3,4-c]pyridine (79.1% yield)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:29]=[CH:28][C:18]([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:20])=[CH:17][N:16]=1.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1>[CH3:30][N:21]([CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:19](=[O:20])[C:18]1[CH:28]=[CH:29][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N(C)C2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-N-(tetrahydro-pyran-4-yl)-nicotinamide (200 mg, 0.51 mmol) in THF (2 mL) was added at 0° C. potassium bis(trimethylsilyl)amide (0.91 M in THF, 614 μL, 0.56 mmol) over a period of 2 min. After stirring for 0.5 h at this temperature iodomethane (41 μL, 0.66 mmol) was added and the resulting suspension was stirred for 2 h at ambient temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (91 mg, 44%) as a white foam. MS: m/e=408.5 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]([N:13]1[C:17]2=[N:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:16]2[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][CH:11]([N:13]1[C:17]2=[N:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=[C:16]2[CH:15]=[C:14]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:12]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCNC(=O)OC(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCN)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 129.9 %

Procedure:
To a solution of diethyl 1-{4-[(tert-butoxycarbonyl)amino]butan-2-yl}-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (1.20 g, 2.77 mmol) in CH2Cl2 (16 mL) is added TFA (4 mL). The mixture is stirred at room temperature for 3 hr. The mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The layers are separated and the aqueous layer is further extracted with ethyl acetate. The combined organic phases are washed with brine, and are dried (Na2SO4) and concentrated in vacuo to afford the title compound (1.20 g, >99%) which is used in the next step without purification. LCMS: 334.75 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.O[CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>CCOCC>[OH:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:17][CH2:6][CH2:7][N:8]=2)=[CH:15][CH:14]=1
Reactant: O=C(NCCO)c1ccc(O)cc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: Oc1ccc(C2=NCCO2)cc1
Yield: 118 %

Procedure:
Thionyl chloride (160 ml) was added to 40 g of N-(2-hydroxyethyl)-4-hydroxybenzamide with evolution of gas. The reaction mixture was ultrasonicated for 1.75 hours, then cooled and diluted with ether. The resulting solid product was collected by filtration, washed with ether and dried overnight in a vacuum oven at 40° C. to give 42.5 g of 4,5-dihydro-2-(4-hydroxyphenyl)oxazole in the form of its hydrochloride salt, m.p. 162°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:6]=[C:7](I)[C:8]=1[O:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[C:38]([Cu])#[N:39]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:21]2[CH2:25][CH2:24][C@H:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[O:22]2)[CH:6]=[C:7]([C:38]#[N:39])[C:8]=1[O:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1
Reactant: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCSc1ccc(Cl)cc1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(C#N)c1OCCSc1ccc(Cl)cc1

Procedure:
trans-2-(3-Methoxy-4-p-chlorophenylthioethoxy-5-iodophenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (2.35 g, 3.58 mmole) and CuCN (0.358 g, 4.30 mmole) in DMF (20 mL) were heated at 140° C. for 16 hours. The reaction mixture was cooled and quenched with water and extracted with ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried over MgSO4, filtered and evaporated in vacuo to oil which was purified by column chromatography (silica, 2:1 hexane/ethyl acetate) (1.79 g, 90.0%). 1H NMR (CDCl3): 1.99 (m, 2H); 2.47 (m, 2H); 3.32 (t, 2H); 3.85 (s, 6H), 3.89 (s, 6H); 4.27 (t, 2H); 5.17 (m, 2H); 6.61 (s, 2H); 7.16 (s, 2H); 7.28 (d, 2H); 7.32 (d, 2H).
Reaction SMILES: Cl.[NH:2]([C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=1)[NH2:3].C(N(CC)CC)C.C[O:19][C:20](=O)[N:21]=[C:22](SC)[C:23]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH2:46][CH2:47][O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:38]=1[F:56])=[N:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[N:35]=[C:34]([CH3:36])[O:33][N:32]=2)=[CH:27][CH:26]=1>CN(C=O)C>[Si:49]([O:48][CH2:47][CH2:46][O:45][C:39]1[C:38]([F:56])=[C:37]([CH:23]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[N:35]=[C:34]([CH3:36])[O:33][N:32]=3)=[CH:29][CH:30]=2)[C:22]2[NH:21][C:20](=[O:19])[N:2]([C:4]3[C:5](=[O:10])[NH:6][CH:7]=[CH:8][N:9]=3)[N:3]=2)[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCO[Si](C)(C)C(C)(C)C)c1F
Reactant: NNc1ncc[nH]c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncc[nH]c3=O)c(=O)[nH]2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
3-Hydrazino-1H-pyrazin-2-one hydrochloride (24 mg) and triethylamine (0.033 ml) were added to 3 ml of a DMF solution containing 70 mg of (2-{3-[2-(t-butyldimethylsilanyloxy)ethoxy]-2-fluoro-5-methoxyphenyl}-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene)carbamic acid methyl ester (Example (200a)). The resulting mixture was stirred at 85° C. for 16 hours and then concentrated under reduced pressure. The residue was dissolved in 5 ml of methanol, and 58 mg of sodium cyanotrihydroborate and 0.056 ml of acetic acid were further added thereto. The mixture was stirred at room temperature for 15 hours. To this reaction mixture, 40 ml of ethyl acetate and 20 ml of water were added. The organic layer was washed with 20 ml of water and then with 20 ml of saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (34 mg).