Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=NCCCN(C)C)C.[OH:12]N1C2C=CC=CC=2N=N1.Cl.[CH:23]([N:26]1[C:30]2[C:31](=[O:40])[NH:32][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:34][C:29]=2[CH:28]=[N:27]1)([CH3:25])[CH3:24].[CH:41]([N:44]1[C:48]2C(=O)N[C:51]3([CH2:57]CN[CH2:54][CH2:53]3)[CH2:52][C:47]=2[CH:46]=[N:45]1)(C)C>CN(C)C=O.O>[CH:23]([N:26]1[C:30]2[C:31](=[O:40])[NH:32][C:33]3([CH2:39][CH2:38][N:37]([C:57]([C:51]4[CH:53]=[CH:54][C:46]5[C:47](=[CH:48][N:44]([CH3:41])[N:45]=5)[CH:52]=4)=[O:12])[CH2:36][CH2:35]3)[CH2:34][C:29]=2[CH:28]=[N:27]1)([CH3:25])[CH3:24]
Reactant: CC(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncc2c1C(=O)NC1(CCN(C(=O)c3ccc4nn(C)cc4c3)CC1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-2H-indazole-5-carboxyllic acid (28 mg, 0.16 mmol) in dry dimethylformamide was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (37 mg, 0.19 mmol) and 1-hydroxybenzotriazole (26 mg, 0.19 mmol) N,N-diisopropylethylamine (84 μL, 0.48 mmol). The reaction mixture was stirred at room temperature for 10 minutes and then 1′-isopropyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one hydrochloride was added (Intermediate 2, 30 mg, 0.12 mmol) and the reaction was stirred for 16 hours. The mixture was poured into chilled water and the resulting precipitate was collected by vacuum filtration. The obtained solid was triturated from diethyl ether to afford 1′-isopropyl-1-(2-methyl-2H-indazole-5-carbonyl)-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(1′H)-one (25 mg). +ESI (M+H) 407.3; 1H NMR (400 MHz, DMSO-d6, δ): 8.41 (s, 1H), 7.85 (s, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 5.40 (m, 1H), 4.18 (s, 3H), 3.60 (br. s., 4H), 2.85 (s, 2H), 1.70 (br. s., 4H), 1.35 (d, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[CH2:21]Cl)=[CH:15][CH:14]=1>C(#N)C.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:23])[CH2:21][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:17][CH:18]=1
Reactant: C1CCNC1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C(CN1CCCC1)Nc1ccc(Br)cc1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
Add potassium carbonate (2.1 g, 15.5 mmol) and pyrrolidine (9.65 mL, 116 mmol) to a solution of N-(4-bromophenyl)-2-chloroacetamide (2.0 g, 7.7 mmol) in acetonitrile (78 mL) at RT. Heat the mixture at 80° C. for 4 h. Cool the mixture to RT, dilute with CH2Cl2, and wash with brine and water. Dry the organic layer over Na2SO4, filter, and concentrate to give 2.17 g (99%) of the title compound. LC-ES/MS m/z (79Br) 283.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].Cl>O>[OH:13][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][C:11]([OH:12])=[O:14]
Reactant: O=C1CCC(c2ccc(F)cc2)O1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC(O)c1ccc(F)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Commercial γ-(p-fluorophenyl)-γ-butyrolactone, 18.0 g. (0.10mole) was added to a solution of 14.0 g. (0.35 mole) of sodium hydroxide in100 ml. of water and the mixture heated at reflux for 40 minutes. After cooling to 0° C., 70 ml. of 6 N hydrochloric acid was added at 0°-15° C. for one hour. The white solid which formed was filtered, washed with pentane and air dried to afford racemic-4-hydroxy-4-(p-fluorophenyl)butyric acid, 18.43 g., (93% yield). When heated to temperatures of about 100° C., the hydroxy acid was converted back to the starting lactone.
Reaction SMILES: [Cl:1][N:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27](Cl)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1.[NH2:41][C:42]1[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]2[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:58])=[O:57])[CH:48]=2)[CH:43]=1>>[Cl:1][N:2]1[N:7]=[C:6]([NH:41][C:42]2[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]3[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=3)[CH:43]=2)[CH:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([S:37]([OH:40])(=[O:39])=[O:38])[C:13]([CH:16]=[CH:17][C:18]3[C:19]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:20][C:21]([NH:24][C:25]4[NH:30][N:29]([Cl:31])[N:28]=[C:27]([NH:41][C:42]5[C:51]([S:52]([OH:55])(=[O:54])=[O:53])=[CH:50][C:49]6[C:44](=[C:45]([S:60]([OH:63])(=[O:62])=[O:61])[CH:46]=[C:47]([S:56]([OH:59])(=[O:57])=[O:58])[CH:48]=6)[CH:43]=5)[CH:26]=4)=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[NH:3]1
Reactant: O=S(=O)(O)c1cc(NC2=CC(Cl)=NN(Cl)N2)ccc1C=Cc1ccc(NC2=CC(Cl)=NN(Cl)N2)cc1S(=O)(=O)O
Reactant: Nc1cc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2cc1S(=O)(=O)O
Product: O=S(=O)(O)c1cc(S(=O)(=O)O)c2cc(NC3=NN(Cl)NC(Nc4ccc(C=Cc5ccc(NC6=CC(Nc7cc8c(S(=O)(=O)O)cc(S(=O)(=O)O)cc8cc7S(=O)(=O)O)=NN(Cl)N6)cc5S(=O)(=O)O)c(S(=O)(=O)O)c4)=C3)c(S(=O)(=O)O)cc2c1

Procedure:
4,4′-Bis-(2,4-dichlorotriazin-6-ylamino)-stilbene-2,2′-disulfonic acid was reacted with 2-aminonaphthalene-3,6,8-trisulfonic acid in a similar manner to Example 5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][N:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1.NC1C2C(C(C3C=CN=C(NS(C4C=CC=CC=4F)(=O)=O)C=3)=O)=CN(C(C)C)C=2N=CN=1>>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([NH:30][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:27]=[CH:26][N:25]=3)=[O:23])=[CH:20][N:19]([CH:31]([CH3:33])[CH3:32])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CC(C)n1cc(C(=O)c2cc(N)ccn2)c2c(N)ncnc21
Agent: CC(C)n1cc(C(=O)c2ccnc(NS(=O)(=O)c3ccccc3F)c2)c2c(N)ncnc21
Product: CC(C)n1cc(C(=O)c2cc(NS(=O)(=O)c3ccccc3F)ccn2)c2c(N)ncnc21

Procedure:
The title compound was prepared from 2-fluoro-benzenesulfonyl chloride (0.53 mL, 0.41 mmol) and (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(4-amino-pyridin-2-yl)-methanone (0.10 g, 0.34 mmol) by procedures analogous to those described for the preparation of N-[4-(4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-pyridin-2-yl]-2-fluoro-benzenesulfonamide. MS: 455.3 (MH+); HPLC Rf: 2.4 min. (HPLC method 2).
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])C)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:19]([NH:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][NH:11][CH3:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCNC(=O)CCCN(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCNC(=O)CCCNC

Procedure:
A solution of the 4-(N-benzyloxycarbonyl-N-methylamino)-N-n-hexylbutyramide thus obtained (6.6 g.) in ethanol (100 ml.) was shaken with hydrogen in the presence of a 10% palladium-on-charcoal catalyst (0.6 g.) for 18 hours, filtered and evaporated to dryness. There was thus obtained as residual oil N-n-hexyl-4-methylaminobutyramide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:16]=[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][N:9]2[N:8]=1.[Cl:17][CH2:18][C:19](=[O:21])[CH3:20]>CCOCC>[Cl-:17].[CH2:18]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:16]=[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][N:9]2[N:8]=1)[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)CCl
Reactant: Cc1ccn2nc(-c3ccccn3)nc2c1
Solvent: CCOCC
Product: CC(=O)C[n+]1ccccc1-c1nc2cc(C)ccn2n1
Product: [Cl-]

Procedure:
2-(2-Pyridyl)-7-methyl-s-triazolo[1,5-a]pyridine (10 g) was added to chloroacetone (30 ml) and the mixture was refluxed for 2 hours. The mixture was cooled, and ether (100 ml) was added. The solid was filtered off, washed with ether, and dried in vacuo to give 1-acetonyl-2-(7-methyl-s-triazolo[1,5-a]pyridin-2-yl)pyridinium chloride. The product was then added to phosphorus trichloride (25 ml) and refluxed for 30 minutes, then cooled, and ether (100 ml) was added. The solid was filtered off, washed with ether, and dried in vacuo, to give 6.8 g of 7,10-dimethyl-pyrido[1,2-a]pyrido[1',2'-1,5]-s-triazolo[3,4-c]pyrazinedium dichloride, mp 186°-188° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[N:22]1[CH2:27][C@H:26]([CH3:28])[C@@H:25]([OH:29])[C@H:24]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:29][C@@H:25]1[C@@H:26]([CH3:28])[CH2:27][N:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:8]([C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:23][C@H:24]1[NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Solvent: ClCCl
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of tert-butyl tert-butoxycarbonyl(4-((3R,4R,5S)-3-((tert-butoxycarbonyl)amino)-4-hydroxy-5-methylpiperidin-1-yl)pyridin-3-yl)carbamate (1.0 equiv.) in DCM (0.20 M) was added TEA (1.7 equiv.), followed by MsCl (1.3 equiv.). The capped solution was stirred at rt for 90 mins. The reaction mixture was quenched with NaHCO3(sat.), and extracted with EtOAc. The organic layer was washed with NaCl(sat.), dried over MgSO4, filtered, concentrated to yield (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-((tert-butoxycarbonyl)amino)-5-methylpiperidin-4-yl methanesulfonate in 99% yield. LC/MS (m/z)=601.3 (MH+), Rt=0.83 min.
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH3:19][N:20]=[C:21]=[O:22].Cl>O.O1CCCC1>[CH3:19][NH:20][C:21]([S:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:22]
Reactant: O=C(O)C(S)c1ccccc1
Reactant: CN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)SC(C(=O)O)c1ccccc1

Procedure:
10.08 g. (60 mM) of α-mercaptophenylacetic acid and 6.6 g. (60 mM) of triethylamine are dissolved in 50 ml. of tetrahydrofuran and 3.42 g. (60 mM) of methylisocyanate dissolved in 20 ml. of tetrahydrofuran are added dropwise with stirring. After stirring for 2 hours, the solvent is drawn off in a vacuum and the oily residue is dissolved in water. The mixture is then acidified with 2N hydrochloric acid and extracted three times each with 20 ml. of ether. After drying off the ether, 10.5 g. of white crystalline DL-[(methylcarbamoyl)thio]phenylacetic acid are obtained, which is recrystallized from ether/petroleum ether, m.p. 128°-129°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[Cl:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (2.37 g, 10.17 mmol) was dissolved in DMF (100 mL). The solution was then heated to 80° C. N-Chlorosuccinimide (1.49 g, 11.1 mmol) was added at 80° C. under Argon gas. After two hours of continuous stirring, the reaction was checked by TLC and LCMS, and found to be incomplete. An additional aliquot of NCS (0.5 g, 3.7 mmol) was added, bringing the reaction to completion after 1.5 hours. While stirring, a portion of water (200 mL) was added to force the product to precipitate out of solution. After the precipitation was complete, the flask containing the solid was cooled in an ice water bath for 10 minutes. The solid was then filtered under vacuum and rinsed with water, yielding 2.4 g (89%) of 4-chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole. This material was used in the next step without purification. LCMS m/z (%)=267 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 8.41 (dd, J1=8 Hz, J2=4 Hz, 1H), 8.22 (d, J=4 Hz, 1H), 7.53 (s, 1H), 7.14 (d, J=12 Hz, 1H), 3.97 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=O)[C:5]=12.Cl.[CH3:13][C:14]([C:17]1[C:22]([F:23])=[CH:21][C:20]([O:24][C@@H:25]2[CH2:28][C@H:27]([NH2:29])[CH2:26]2)=[CH:19][C:18]=1[F:30])([CH3:16])[CH3:15]>>[CH3:16][C:14]([C:17]1[C:18]([F:30])=[CH:19][C:20]([O:24][C@@H:25]2[CH2:26][C@H:27]([NH:29][CH2:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[CH2:28]2)=[CH:21][C:22]=1[F:23])([CH3:13])[CH3:15]
Reactant: CC(C)(C)c1c(F)cc(O[C@H]2C[C@@H](N)C2)cc1F
Reactant: O=Cc1cccn2ccnc12
Agent: Cl
Product: CC(C)(C)c1c(F)cc(O[C@H]2C[C@@H](NCc3cccn4ccnc34)C2)cc1F

Procedure:
Prepared similarly to Example 1 from imidazo[1,2-a]pyridine-8-carbaldehyde and cis-3-{[4-(1,1-dimethylethyl)-3,5-difluorophenyl]oxy}cyclobutanamine hydrochloride. LCMS (System B): tRET=3.28 min; MH+ 386
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]([CH2:20][CH:21]([C:27]([O:29]CC)=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1.O.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:25]([O:24][C:22]([CH:21]([CH2:20][C:19]1[CH:32]=[CH:33][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:17][CH:18]=1)[C:27]([OH:29])=[O:28])=[O:23])[CH3:26]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylmalonate (4.60 g, 10.2 mmol) obtained in Example 55 was dissolved in a mixed solvent of ethanol (50 ml) and tetrahydrofuran (25 ml), and the mixture was stirred at room temperature for 18 hr. The solvent was evaporated to give a crude solid. Water (20 ml) and 1N sodium hydroxide (30 ml) were added to dissolve said crude solid. 1N Hydrochloric acid was added at 0° C., and the mixture was extracted three times with ethyl acetate (30 ml). The extracted organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness to give a crude title compound (4.7 g), which was purified and concentrated by silica gel column chromatography (developing solvent; chloroform:methanol=100:1→50:1) to give the title compound. This compound was dissolved in 1N sodium hydroxide (10 ml) and washed twice with ethyl acetate (30 ml). 1N Hydrochloric acid (15 ml) was added to the aqueous layer, and the mixture was extracted three times with ethyl acetate (30 ml). The extracted organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness to give the title compound (2.91 g, yield 67%) as white crystals.
Reaction SMILES: C(O[C:6](=[O:22])[NH:7][C:8]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])([CH2:12][OH:13])[CH:9]([F:11])[F:10])(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[Cl:29][CH:30](C)[C:31](Cl)=O>Cl.O1CCOCC1.ClCCl>[Br:20][C:18]1[CH:17]=[CH:16][C:15]([F:21])=[C:14]([C:8]([NH:7][C:6](=[O:22])[CH:30]([Cl:29])[CH3:31])([CH2:12][OH:13])[CH:9]([F:10])[F:11])[CH:19]=1
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Reactant: CC(Cl)C(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(Cl)C(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester [Example 42 step c)] (2.21 g, 5.75 mmol) was dissolved in 20 mL HCl solution 4 mol/L in dioxane and stirred at room temperature for 60 minutes. The reaction mixture was evaporated to give a white solid which was directly taken up in 15 mL dichloromethane. 20 mL aqueous Na2CO3 solution (10% w/w) was added and the emulsion was cooled to 0-5° C. Racemic 2-chloro-propionyl chloride (787 mg, 6.20 mmol) was added dropwise and the reaction mixture was slowly warmed to room temperature. After 30 minutes, the layers were separated and washed with dichloromethane. The organic layers were combined, dried over Na2SO4 and evaporated. The crude product was purified on a silica gel column by eluting with heptanes/EtOAc 3/1→2/1 to give 632 mg of the first eluting and 619 mg of the second eluting diastereomer.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:17])([F:16])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)C.[NH2:19][NH2:20].O>CO>[F:16][C:5]([F:17])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:4]([NH:19][NH2:20])=[O:3]
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 45 °C
Yield: 84.7 %

Procedure:
To a solution of difluoro-quinolin-6-yl-acetic acid ethyl ester (5.5 g, 21.9 mmol) in methanol (85 mL) was added hydrate hydrazine (5.3 mL, 109.5 mmol). The mixture was heated to 45° C. for 10 min., cooled to room temperature, concentrated, and taken up in dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a light orange solid (4.4 g, 85%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[CH2:20][C:19]2[C:18]([C:21]#[N:22])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:13]1.Cl.[CH2:24]([N:31]([CH2:35][CH2:36]Cl)[CH2:32][CH2:33]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH2:24]([N:31]1[CH2:35][CH2:36][C:20]2([C:19]3[C:18]([C:21]#[N:22])=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]2=[O:11])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#Cc1cccc2c1CC(=O)N2
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cccc2c1C1(CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
A 1.0M THF solution of NaHMDS (158 mL, 158 mmol) at −78° C. was added dropwise to a stirred solution of 2-oxoindoline-4-carbonitrile (6.0 g, 37.3 mmol) in THF (100 mL) under N2. After stirring at −78° C. for 30 minutes, N-benzylbis(2-chloroethyl)amine hydrochloride (10.9 g, 41.2 mmol) was added as a solid. The reaction mixture was stirred at −78° C. for 30 minutes and then allowed to warm to room temperature. The reaction mixture was then heated to reflux for 12 hours. After cooling to 0° C., the reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organics layers were washed with brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography (1:1 hexanes:EtOAc to EtOAc to give 1′-benzyl-2-oxospiro{indoline-3,4′-piperidine]-4-carbonitrile (4.90 g, 50%) as a solid. LCMS (APCI+) m/z 318 [M+H]+; Rt=2.41 min.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25]O)[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:46]1(=[O:56])[NH:50][C:49](=[O:51])[C:48]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:47]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:7][NH:8][C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][C:19]4[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][N:50]5[C:46](=[O:56])[C:47]6[C:48](=[CH:52][CH:53]=[CH:54][CH:55]=6)[C:49]5=[O:51])[CH:20]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Oc2ccc3nc(NCC4CCCCC4)oc3c2)ccn1
Reaction time: 16 h

Procedure:
To a solution of the (4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methanol (20 mg, 0.057 mmol, 1.0 eq) in 2 mL of THF was added triphenyl phosphine (22 mg, 0.085 mmol, 1.5 eq), phthalimide (12.5 mg, 0.085 mmol, 1.5 eq) and diisopropyl azodicarboxylate (17 mg, 0.085 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at that temperature for 16 hours. Then the solvent was removed. The crude product was purified by preparative TLC sheet to give 2-((4-(2-(cyclohexylmethylamino)benzo[d]oxazol-6-yloxy)pyridin-2-yl)methyl)isoindoline-1,3-dione.
Reaction SMILES: C(OC1C=CC([C:10]2[S:14][C:13]3[CH:15]=[C:16](OCC)[CH:17]=[CH:18][C:12]=3[CH:11]=2)=CC=1)C.COC1C=C(C=C(OC)C=1OC)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-].O>C(Cl)Cl.CCOC(C)=O>[S:14]1[CH:10]=[CH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]1=2
Reactant: CCOc1ccc(-c2cc3ccc(OCC)cc3s2)cc1
Agent: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2sccc2c1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
To a well-stirred solution of 2-(4'-ethoxyphenyl)-6-ethoxybenzo[b]thiophene (0.095 g, 0.32 mmol) and 3,4,5-trimethoxybenzoyl chloride (0.159 g, 0.69 mmol) in CH2Cl2 (15 mL) was added AlCl3 (0.139 g, 1.04 mmol) portion-wise over a 5 minute period. After 30 min., water was added, and the product was isolated initially by extraction with CH2Cl2 and subsequently by extraction with EtOAc. The organic layers were separately washed with brine and then combined and dried over MgSO4. Purification by flash chromatography (silica gel, 80:20 hexane/EtOAc) afforded benzo[b]thiophene (0.110 g, 0.2 mmol, 69%) as an off-white solid. 1H-NMR (CDCl3, 360 Mhz) δ 7.65 (d, J=8.9 Hz, 1H, ArH), 7.32 (d, J=2.3 Hz, 1H, ArH), 7.29 (d, J=8.8 Hz, 2H, ArH), 7.06 (s, 2H, ArH), 7.00 (dd, J=8.9, 2.4 Hz, 1H, ArH), 6.73 (d, J=8.7 Hz, 2H, ArH), 4.12 (q, J=7.0 Hz, 2H, --CH2), 3.97 (q, J=6.9 Hz, 2H, --CH2), 3.83 (s, 3H, --OCH3), 3.73 (S, 6H, --OCH3), 1.47 (t, J=6.9 Hz, 3H, --CH3), 1.37 (t, J=7.0 Hz, 3H, --CH3).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14](Cl)=[N:13][C:12]=1Cl)[CH3:8].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[N:13][C:12]=1[O:4][C:1]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)[CH3:8]
Reactant: CCOC(=O)c1ccc(Cl)nc1Cl
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(C#N)cc1
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
Potassium carbonate 1.58 g (11.5 mmol) was added to a stirred solution of 2,6-dichloro-nicotinic acid ethyl ester 1.0 g (4.6 mmol) in 5 ml of DMF and stirred for 10 min. 4-Hydroxy-benzonitrile 1.36 g (11.5 mmol), dissolved in 5 ml of DMF, was added dropwise to the stirred DMF solution and the flask was stirred at 80° C. for 4 h. The reaction mixture was poured into ice-cold water and the result was partitioned using ethyl acetate. The organic phase was washed with 1 M of Na2CO3 and saturated brine solution, dried over sodium sulphate and concentrated. The oily residue was purified by column chromatography using hexane-ethyl acetate (10:2) to afford 1.6 g of the required product. Percentage purity: 84.8%, (M+1)=385.1. 1H NMR (DMSO-d6): 1.36 (3H, t), 4.22 (214, q), 6.78 (1H, d), 7.06 (4H, d), 7.58 (4H, d), 8.21 (1H, d).