Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[C:14]1([C@@H:12]([NH:11][CH:10]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](NC(c1ccncc1)c1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: C[C@H](NC(c1ccncc1)c1cccc(N)c1)c1ccccc1
Yield: 74.8 %

Procedure:
In a similar manner to that described in Example (1b), isomer B of N-[(3-nitrophenyl)-4-pyridylmethyl]-[(S)-1-phenylethyl]amine (1.02 g), nickel chloride hexahydrate (1.47 g) and sodium borohydride (470 mg) were reacted, to afford isomer B of the title compound (694 mg) as a pale yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:60]=[C:61]([CH:64]=[CH:65][CH:66]=2)[C:62]#[N:63])[CH2:54][CH2:53]1>CN(C=O)C.O>[C:62]([C:61]1[CH:60]=[C:59]([NH:58][CH:55]2[CH2:56][CH2:57][N:52]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:18]3[CH:17]=[C:16]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:20][N:19]=3)=[O:22])[CH2:53][CH2:54]2)[CH:66]=[CH:65][CH:64]=1)#[N:63]
Reactant: N#Cc1cccc(NC2CCNCC2)c1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cccc(NC2CCN(C(=O)CNC(=O)c3cc(-c4ccccc4)[nH]n3)CC2)c1
Reaction time: 8 h
Yield: 42 %

Procedure:
DIPEA (135 mg, 1.0 mmol) was added to a stirred of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (150 mg, 0.7 mmol) in DMF (4 mL) followed by HOBt (108 mg, 0.8 mmol) and EDCI.HCl (160 mg, 0.8 mmol). After 2 minutes of stirring 3-(piperidin-4-ylamino)-benzonitrile dihydrochloride (prepared according to Step 2 and 5 of the General Scheme) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine and concentrated. The residue was purified by column chromatography (using neutral alumina and 5% MeOH in CHCl3) to afford 91 mg (42% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(3-cyano-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 429.2, 92.9%, 1H NMR (300 MHz, DMSO-d6): δ 8.0 (m, 1H), 7.8 (m, 2H), 7.5 (m, 2H), 7.4 (m, 1H), 7.2 (m, 1H), 7.1 (b, 1H), 6.9 (m, 2H), 6.2 (m, 1H), 4.3 (m, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.4 (m, 1H), 1.2 (m, 1H).
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1Br
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Product: COc1ccccc1N1N(C2CCCCCCC2)C(=O)C1(C)C

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 5 of Example 73 and 1-bromo-2-methoxybenzene was used for a similar reaction and treatment as Example 181, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=[O:4].[N+:21]([C:24]1[S:28][C:27]([C:29](O)=[O:30])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[F:20][C:16]1[CH:15]=[C:14]([CH:6]([NH:5][C:3]([CH2:2][NH:1][C:29]([C:27]2[S:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[O:30])=[O:4])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])s1
Reactant: NCC(=O)NC(c1cccc(F)c1)c1cccc(F)c1
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])s1)NC(c1cccc(F)c1)c1cccc(F)c1

Procedure:
Prepared in analogy to example 1.12 from 2-amino-N-[bis-(3-fluoro-phenyl)-methyl]-acetamide (example 3.4) and 5-nitro-thiophene-2-carboxylic acid.
Reaction SMILES: NC[C@@H](C1C=CC(O)=C2C=1C=CC(=O)N2)O[Si](C(C)(C)C)(C)C.[N:24]([CH2:27][C@@H:28]([C:37]1[CH:38]=[CH:39][C:40]([O:48]CC2C=CC=CC=2)=[C:41]([NH:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=1)[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[N+]=[N-]>>[NH2:24][CH2:27][C@@H:28]([C:37]1[CH:38]=[CH:39][C:40]([OH:48])=[C:41]([NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH:42]=1)[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 2, using Intermediate 17 in place of Intermediate 1. The compound was used with no further purification. ES/MS calcd. for C15H29N2O4SSi+ 361.2. Found m/z=361 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]([F:28])([F:27])[C:13]1[C:14]([N:19]2[CH:23]=[C:22]([C:24](=[O:26])[CH3:25])[CH:21]=[N:20]2)=[N:15][CH:16]=[CH:17][CH:18]=1.[F:29][C:30]([F:37])([F:36])[C:31](OCC)=[O:32].Cl>C1COCC1>[F:29][C:30]([F:37])([F:36])[C:31](=[O:32])[CH2:25][C:24]([C:22]1[CH:21]=[N:20][N:19]([C:14]2[C:13]([C:12]([F:11])([F:27])[F:28])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:23]=1)=[O:26]
Reactant: CC(=O)c1cnn(-c2ncccc2C(F)(F)F)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1cnn(-c2ncccc2C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 201.4 %

Procedure:
Alternatively, lithium bis(trimethylsilyl)amide (1.0M solution in THF, 1.1 mL, 1.1 mmol) was slowly added to a solution of 1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-ethanone (240 mg, 0.94 mmol) in 2 mL anhydrous THF at −78° C. under nitrogen. The mixture was then allowed to warm to −20° C. and kept at −20° C. to −5° C. for 3 hrs. After this period of time the mixture was cooled to −78° C. and to it was added ethyl trifluoroacetate (200 mg, 0.41 mmol). The mixture was next allowed to warm to ambient temperature overnight. 1N aqueous HCl was carefully added to adjust the pH 2. Two layers were separated and the aqueous layer was extracted with chloroform three times. The extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo to give 4,4,4-trifluoro-1-[1-(3-trifluoromethyl-pyridin-2-yl)-1H-pyrazol-4-yl]-butane-1,3-dione as a yellow solid (290 mg, 88% yield). The product was used for the next step without purification. 1H-NMR (400 MHz, CDCl3): δ 6.35 (s, 1H), 7.59 (dd, 1H, J=4.80, J=7.83), 8.21 (s, 1H), 8.28 (dd, 1H, J=1.77, J=3.80), 8.75 (dd, 1H, J=4.80, J=1.77), 8.76 (d, 1H, J=0.51).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:9][CH:8]=1.[NH3:26]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]3[C:21]([C:22]([NH2:26])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[CH:11][CH:12]=1
Reactant: N
Reactant: COC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3)oc12
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3)oc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
Methyl 2-(4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxylate (170 mg, 0.5 mmol) was added to ammonia in methanol (30 mL) and the mixture was stirred at room temperature for 3 days. Then the solid was filtered, washed with methanol, dried in vacuum. 110 mg of solid of 2-(4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide was obtained. Yield: 69%. 1H-NMR (400 MHz, DMSO-d6) δ 7.43-7.45 (m, 1H), 7.50-7.53 (t, J=7.6 Hz, 1H), 7.83-7.85 (m, 1H), 7.89 (brs, 1H), 7.95-8.01 (m, 3H); 8.12-8.14 (d, J=8.0 Hz, 1H); 8.36-8.44 (q, 3H); 8.74-8.75 (m, 1H); LC-MS (ESI) m/z: 316 (M+1)+.
Reaction SMILES: C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:25]=[C:26]1[NH:30][CH2:29][CH:28]([C:31]([OH:33])=O)[S:27]1.[N+]([O-])(O)=O.[N+:38]([O:41][CH2:42][CH2:43][NH2:44])([O-:40])=[O:39]>O1CCCC1>[N+:38]([O:41][CH2:42][CH2:43][NH:44][C:31]([CH:28]1[S:27][C:26](=[O:25])[NH:30][CH2:29]1)=[O:33])([O-:40])=[O:39]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NCC(C(=O)O)S1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Product: O=C1NCC(C(=O)NCCO[N+](=O)[O-])S1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.4 %

Procedure:
0.85 ml of triethylamine and 0.53 ml of diphenylphosphoryl azide were added, whilst ice-cooling, to a suspension of 0.30 g of 2-oxothiazolidine-5-carboxylic acid (prepared as described in Preparation 3) and 0.41 g of N-(2-nitrooxyethyl)amine nitrate in 10 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. The crude crystals thus obtained were triturated with diisopropyl ether, collected by filtration and washed to give 0.40 g of the title compound as a colorless powder, melting at 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]1[N:14]([CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])[CH2:13][CH2:12][N:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH:10]12>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][N:14]2[CH2:13][CH2:12][N:11]3[CH2:21][CH2:22][CH2:23][CH2:24][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)CCCN1CCN2CCCCC2C1
Product: O=C(CCCN1CCN2CCCCC2C1)Nc1ccc(Cl)cc1

Procedure:
The procedure is as for Example 2 using as substrate 4-chloroaniline and the compound obtained in Step B of Example 2.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH3:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([CH3:24])=[CH:20][CH:21]=2)[C:16]1=O>O>[CH3:14][C:15]1([CH2:1][OH:4])[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[C:19]([CH3:24])[CH:18]=2)[CH2:23]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(c1)C(=O)C(C)C2
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)CC(C)(CO)C2
Reaction time: 2 h
Yield: 215.1 %

Procedure:
147.53 g of K2CO3, 875 g of toluene and 350 g of 2,6-dimethyl indanone were introduced, under nitrogen, into a Schmizo-type 1.5 l vessel provided with a condenser and a mechanical stirrer. The mixture was heated to 51°. 122.45 g of Formcel® 55% (origin: Hoechst) were then added over a period of 1 h. The mixture was stirred continuously at 51° for 2 h. The reaction medium was then cooled to 24° and 350 g of water were added. After being stirred for 10 mins, the mixture was decanted, then washed 3 times with water. Concentration in vacuo produced 404.71 g of raw product pure to 97.6% (GC).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[CH:4][CH:3]=1.[CH3:15][C:16]1[N:17]([CH2:25][CH2:26][CH2:27]CO)[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:8][C:9]([O:11][CH2:12][CH2:27][CH2:26][CH2:25][N:17]2[C:18]3[CH:23]=[CH:22][N:21]=[CH:20][C:19]=3[N:24]=[C:16]2[CH3:15])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1nc2cnccc2n1CCCCO
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: Cc1nc2cnccc2n1CCCCOC(=O)CC(=O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Methyl 4-fluorobenzoylacetate (0.78 g, 4 mM) and 4-(2-methylimidazo[4,5-c]pyrid-1-yl)butanol (0.82 g, 4 mM--see Preparation 16) were heated at reflux in toluene (100 cm3) allowing the toluene to reduce to about 20 cm3 over a period of 2 hours. The remaining toluene was removed in vacuo and the residue purified by column chromatography on silica (Merck "Kieselgel 60"--Trade Mark) eluting with dichloromethane:methanol 19:1. Evaporation of the appropriate fractions gave the title compound as a colourless oil, (1.05 g, 71%).
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.[F:40][C:41]1[C:46]([C:47]([F:50])([F:49])[F:48])=[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]([C:47]([F:50])([F:49])[F:48])[C:41]=2[F: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(C(F)(F)F)c1F
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(C(F)(F)F)c3F)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-fluoro-3-(trifluoromethyl)phenyl)boronic acid gave 156. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.56 (t, J=7.7 Hz, 1H), 7.85 (s, 1H), 7.79 (t, J=7.3 Hz, 1H), 7.57 (s, 2H), 7.49 (t, J=7.9 Hz, 1H), 4.91-4.82 (m, 1H), 4.67-4.49 (m, 1H), 4.42-4.26 (m, 1H), 4.21-4.00 (m, 1H), 3.77 (s, 3H), 2.13-2.01 (m, 1H), 1.90-1.67 (m, 4H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:40]=[CH:39][C:18]([NH:19][C:20]2[CH:36]=[C:35]([F:37])[C:34]([F:38])=[CH:33][C:21]=2[C:22]([NH:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:19]2[C:20]3[C:21](=[CH:33][C:34]([F:38])=[C:35]([F:37])[CH:36]=3)[C:22](=[O:23])[N:24]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:1]2=[O:2])=[CH:39][CH:40]=1
Reactant: COc1ccc(Nc2cc(F)c(F)cc2C(=O)NOCc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)cc1
Yield: 45.2 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (6.7 g, 41.6 mmol) and crude 2-(4-methoxy-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example V, 8.0 g, 20.8 mmol) provided 3.86 g of the title compound as a solid, mp 211-212° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>C(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:12](=[O:13])[N:11]([CH3:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: OCc1ccc(O)cc1
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
To a solution of 4-hydroxymethylphenol (10 mmol) and 4-diazabicyclo[2.2.2]octane (DABCO) (10 mmol) in CH2Cl2 (30 mL) was added N-methyl-N-phenylcarbamoyl chloride (10 mmol). The reaction mixture was stirred for 16 hours at rt, added CH2Cl2 (20 mL) and washed with 1M aqueous HCl and brine. The organic phase was dried (MgSO4) and evaporated to give the crude product which was purified by FC (Quad flash 40 EtOAc-Heptane 1:1) to give 2.18 g (85%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18][S:19]([N:22]([CH3:46])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:37]2[C:32]([CH:33]=[N:34][C:35](OS(C(F)(F)F)(=O)=O)=[N:36]2)=[CH:31][CH:30]=1)(=[O:21])=[O:20].C(N(CC)C(C)C)(C)C.COCC(O)C>>[OH:13][CH:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:35]3[N:34]=[CH:33][C:32]4=[CH:31][CH:30]=[C:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]([CH3:46])[S:19]([CH3:18])(=[O:21])=[O:20])[N:37]4[N:36]=3)=[C:3]([O:16][CH3:17])[CH:4]=2)[CH2:8][CH2:9]1
Reactant: COc1cc(CN2CCC(O)CC2)ccc1N
Reactant: CN(c1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12)S(C)(=O)=O
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CN2CCC(O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3N(C)S(C)(=O)=O)n2n1
Temperature: 120 °C

Procedure:
Into an 8-dram vial, [1-(4-Amino-3-methoxy-benzyl)-piperidin-4-ol (0.102 g, 0.430 mmol), Trifluoro-methanesulfonic acid 7-[2-(methanesulfonyl-methyl-amino)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (88.0 mg, 0.195 mmol), N,N-Diisopropylethylamine (0.0749 mL, 0.430 mmol), and 1-Methoxy-2-propanol (0.70 mL, 7.2 mmol) were added. The reaction mixture was heated at 120° C. for 6 hours. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give N-(2-{2-[4-(4-Hydroxy-piperidin-1-ylmethyl)-2-methoxy-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-phenyl)-N-methyl-methanesulfonamide a yellow solid (92 mg, 72%). LCMS (E/I+) 537.11 (M+H). NMR 1H (DMSO-d6)-9.16 (bs, 1H), 9.00 (s, 1H), 8.07-8.12 (m, 1H), 7.95-8.01 (m, 1H), 7.86 (s, 1H), 7.64-7.70 (m, 1H), 7.52-7.58 (m, 1H), 7.19 (d, 1H, J=9.96 Hz), 7.03 (d, 1H, J=4.60 Hz), 7.01 (d, 1H, J=4.60 Hz), 6.90-7.00 (m, 1H), 4.24 (dd, 2H, J=4.64, 16.65 Hz), 2.80-4.00 (m, 15H), 1.40-2.00 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[CH2:11]([NH2:13])[CH3:12].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl.CO>[CH2:11]([NH:13][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:12]
Reactant: CCN
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCNCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
To a mixture of anisaldehyde (15.6 g, 115 mmol) and ethylamine (2.0M in THF, 87 mL, 174 mmol) in 1,2-dichloroethane (450 mL) was added glacial acetic acid (10.0 mL, 174 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min and then cooled to 0° C. with ice bath. NaBH(OAc)3 (36.9 g, 174 mmol) was added portionwise and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was diluted with a basic solution (10 g NaOH in 100 mL of water) to make the solution slightly basic. This aqueous layer was extracted with ether. The combined extracts were washed with water, brine, dried and concentrated. The residue was chromatographed on silica gel (elution with 5% MeOH in CH2Cl2 and then 50% MeOH in CH2Cl2 containing 4% Et3N) to afford the product (11.2 g, 59% yield) as an oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:48]=[CH:49][CH:50]=2)[CH2:33][NH:34][C:35]2[CH:47]=[CH:46][C:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O.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>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:31]=[C:32]([CH:48]=[CH:49][CH:50]=3)[CH2:33][NH:34][C:35]3[CH:47]=[CH:46][C:38]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])=[CH:37][CH:36]=3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3cccc(CNc4ccc(C(=O)OC(C)(C)C)cc4)c3)nc3scnc23)cc1OC
Yield: 40.8 %

Procedure:
Under N2 atmosphere, 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (100 mg, 0.31 mmol), tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylamino)benzoate (150 mg, crude), Pd(PPh3)4 (30 mg, 0.026 mmol) and Na2CO3 (150 mg, 1.41 mmol) in 5 mL of water was added in 30 mL of 1,4-dioxane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (5:1) to give tert-butyl 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzylamino)benzoate (72 mg, 41%) as a yellow sold. 1H NMR (300 MHz, DMSO): δ 8.87 (s, 1H), 8.54-8.47 (m, 2H), 7.86-7.82 (m, 3H), 7.49-7.28 (m, 2H), 7.27-7.23 (m, 1H), 6.94 (d, 1H, J=8.7 Hz), 6.65-6.62 (m, 2H), 4.49 (s, 2H), 4.16 (s, 3H), 4.13 (s, 3H). LC-MS: 570 [M+H]+, tR=1.83 min. HPLC: 98.31% at 214 nm, 98.91% at 254 nm, tR=8.06 min.
Reaction SMILES: [CH3:1][NH:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2S\1.OO.[S:22]([O-:25])([O-])=[O:23].[Na+].[Na+]>C(O)(=O)C>[CH3:1][NH:2]/[C:3](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:4]1\[C:5](=[O:13])[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[S:22]\1(=[O:25])=[O:23]
Reactant: CN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CN/C(=C1\C(=O)c2ccccc2S1(=O)=O)c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 6.0 gm (0.0224 mol) of (E)-2-[(methylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one, 100 ml of glacial acetic acid and 3.5 ml (0.034 mol) of an aqueous 30% hydrogen peroxide solution was heated at 50° C. for four hours while stirring and then allowed to stand overnight at room temperature. After the addition of 40 ml of a 10% sodium sulfite solution, the mixture was concentrated by evaporation in vacuo, and the residue was suspended in 200 ml of water. The solid material precipitated thereby was suction-filtered off and then broken down into its constituents by column chromatography on 300 gm of silica gel, using 1,2-dichloroethane/ethyl acetate (97:3 v/v) as the eluant. By evaporating the appropriate fractions, 2.0 gm (33% of theory) of pale yellow (E)-2-[(methylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one-1-oxide, m.p. 205-206° C (decomposition) from ethanol), and 0.10 gm (1.5% of theory) of light yellow (E)- 2-[(methylamino)phenylmethylene]-benzo[b]-thiophen-3(2H)-one-1,1-dioxide, m.p. 302°-303° C., were obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:22])[C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=1)=[CH:6][CH:5]=2.[Li+].[OH-]>C1COCC1.CO>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:22])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)C(C)c1ccc(-c2ccc3[nH]c(C)cc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2cc(-c3ccc(C(C)C(=O)O)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a solution of 16d (24 mg, 82 μmol) in THF (2 mL) and MeOH (0.5 mL) was added a 1.0N aqueous solution of LiOH (0.2 mL, 200 μmol) and the resulting mixture was stirred at room temperature overnight. The reaction was diluted with a 25% aqueous solution of NH4OAc and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. Purification by flash chromatography (30:70:1 EtOAc/hexane/AcOH) gave 23 mg of the title compound as a light yellow gum.