Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.C1N=CN([C:15](N2C=NC=C2)=[O:16])C=1>C1COCC1>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:8]2[NH:9][C:15]1=[O:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1ncccc1N
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2cccnc21
Yield: 82.6 %

Procedure:
A solution of N2-methylpyridine-2,3-diamine (7 g) and CDI (13.82 g) in THF (100 mL) was refluxed for 5 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (7 g) as a light brown solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10]1[CH:19]=[C:18]([O:20]C)[C:17]2[C:12](=[C:13]([O:24][CH3:25])[CH:14]=[CH:15][C:16]=2[O:22][CH3:23])[C:11]=1[O:26]C)[CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[N+]([O-])([O-])=O.[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[CH2:1]([O:3][CH:4]([C:10]1[C:11](=[O:26])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[C:16]([O:22][CH3:23])[CH:15]=[CH:14][C:13]=2[O:24][CH3:25])[CH2:5][CH2:6][CH:7]([CH3:8])[CH3:9])[CH3:2]
Reactant: CCOC(CCC(C)C)c1cc(OC)c2c(OC)ccc(OC)c2c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(CCC(C)C)C1=CC(=O)c2c(OC)ccc(OC)c2C1=O
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
600 mg (3.4 mmole) of 2-(1-ethoxy-4-methylpentyl)-1,4,5,8-tetramethoxynaphthalene was dissolved in 25 ml of acetonitrile and then a solution of 8.6 g (17 mmole) of cerium (IV) ammonium nitrate dissolved in 25 ml of distilled water was added dropwise thereto over 30 minutes through a dropping funnel in a cooling bath (0°-5° C.). The reaction mixture was stirred at normal temperature for 2 hours. After adding 60 mg of distilled water thereto, the reaction mixture was extracted twice with dichloromethane solvent, dried over anhydrous magnesium sulfate and then filtered through filter paper. The resulting filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (silica gel 4.0×15 cm) using the solvent condition which increases the amount of ethylacetate so that the n-hexane/ethylacetate ratio can vary from 10:1 to 1:1, to obtain 300 mg of the title compound as a yellow precipitate.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=2[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:16])=[O:8])[CH2:4][O:3]1.C(=O)([O-])[O-].[C:43]([O:46][CH2:47][CH2:48]Br)(=[O:45])[CH3:44].O>CS(C)=O>[C:43]([O:46][CH2:47][CH2:48][N:9]([C:10]1[C:11]([I:37])=[C:12]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C:13]([I:31])=[C:14]([C:29]=1[I:30])[C:15]([NH:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][O:21][C:22](=[O:24])[CH3:23])=[O:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:38])([CH3:1])[O:6]1)=[O:8])(=[O:45])[CH3:44]
Reactant: CC(=O)OCCBr
Reactant: CC(=O)OCc1c(I)c(NC(=O)C2COC(C)(C)O2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 45 °C
Reaction time: 17 h

Procedure:
5-(2,2-Dimethyl-1,3-dioxolane-4-carboxamido)-3-acetoxymethyl-N-(2,3-diacetoxypropyl)-2,4,6-triiodobenzamide (0.44 a, 0.50 mmol) was dissolved in dimethylsulfoxide (3 ml) and cesmium carbonate (0.33 g, 1.0 mmol) was added. 2-Bromoethyl acetate (0.25 g, 2.5 mmol) was added dropwise. The mixture was stirred at 45° C. for 17 h then added slowly into water (50 ml). A precipitate was formed, filtered off and the filtercake was dissolved in chloroform (60 ml). The organic phase was washed with water (2×30 ml), then dried (Na2SO4) and evaporated to a solid product. Yield: 0.46 g (93%).
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].[Mg].[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=1[CH:15]=[O:16].[NH4+].[Cl-]>O1CCCC1>[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=1[CH:15]([OH:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CBr
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CC(O)C1=C(C)CCCC1(C)C
Reaction time: 2 h

Procedure:
In an atmosphere of nitrogen, a solution of 280 g. of 1-bromopropene in 430 ml. of tetrahydrofuran was added dropwise at 63°-65° into a suspension of 53.3 g. of magnesium turnings in 660 ml. of tetrahydrofuran. During the addition the reflux condenser fitting the reaction vessel was cooled to -40° to -50° in order to prevent escaping of the vapours of unreacted 1-bromopropene. The mixture was stirred for an additional 21/2 hours at 60°-62° after which it was cooled to 0°. A solution of 278 g. of β-cyclocitral in 350 ml. of tetrahydrofuran was then added dropwise between 0° and 7°. The mixture was allowed to stand overnight then it was poured onto a mixture of ice and saturated aqueous NH4Cl solution. The organic layer was removed and the aqueous phase extracted with petroleum-ether (b.p. 30°-50°). The combined extracts were washed as usual, dried and then evaporated under vacuum. The residue gave 350 g. of crude 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4](O)=[O:5].[BH4-].[Na+].B(F)(F)F>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CO)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
A solution of 2-fluoro-5-methoxy-4-nitrobenzoic acid (Compound 130E, 1.60 g, 7.44 mmol) in THF (23.6 mL) is slowly charged with sodium borohydride (0.633 g, 16.8 mmol) and stirred for 5 minutes. A solution of boron trifluoride, ethyl ether complex (0.895 mL, 7.26 mmol) in THF (7.85 mL) is added to the reaction mixture. The resulting solution is heated at reflux for 4 h. The reaction mixture was cooled to 0° C., then quenched with ice (15 mL) and diluted with ether (25 mL) and 2 N NaOH (10 mL). The ether layer was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an off-white solid, 1.45 g (97% yield). This material was used without any further purification. 1H NMR (CDCl3, 400 MHz): δ=3.99 (s, 3 H), 4.86 (s, 2 H), 7.29 (d, J=5.81 Hz, 1 H), 7.64 (d, J=9.09 Hz, 1 H). MS (ES+): m/z 202.05 [MH+] (TOF, polar).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]2[S:15][CH:14]=[C:13]([CH2:16][CH2:17][CH3:18])[C:8]=2[N:9]=[C:10](Cl)[N:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:22])[CH:20]=[CH2:21].C(=O)([O-])O.[Na+]>>[CH2:19]([NH:22][C:10]1[N:11]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]2[S:15][CH:14]=[C:13]([CH2:16][CH2:17][CH3:18])[C:8]=2[N:9]=1)[CH:20]=[CH2:21]
Reactant: C=CCN
Reactant: CCCc1csc2c(NC(C)(C)C)nc(Cl)nc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC(C)(C)C)c2scc(CCC)c2n1
Yield: 76.5 %

Procedure:
173 mg (0.61 mmol) of 4-t-butylamino-2-chloro-7-propylthieno[3,2-d]pyrimidine and 557 mg (9.8 mmol) of allylamine were heated in a sealed tube at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 142 mg (yield: 76.3%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:32])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2.[OH-].[Li+].Cl>O1CCCC1.O>[F:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH:17]([CH3:18])[CH3:19])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)=[C:8]2[CH3:32]
Reactant: COC(=O)COc1ccc(F)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(F)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A solution of [8-fluoro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.062 g) in tetrahydrofuran (0.70 mL) and water (0.70 mL) was treated with lithium hydroxide (0.033 g), and the resulting mixture was stirred at room temperature. After 24 hours, the mixture was treated with additional lithium hydroxide (0.033 g) and stirring continued for 16 hours. The mixture was cooled to 0° C., acidified with 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate (3×5.0 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (2.0 mL), dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (40:60 to 19:1 by volume) gave title compound as a yellow solid (0.015 g).
Reaction SMILES: C(O[C:6]([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[C:20](=[O:21])[CH2:19][CH2:18][CH:17]2C)[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.[CH3:47][N:48]1[CH2:53]CNC[CH2:49]1>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:17][CH2:18][CH2:19][C:20]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:6][CH2:49][N:48]([CH3:53])[CH2:47][CH2:40]3)=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: CN1CCNCC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCN(C)CC3)CC2)c(C)c1
Yield: 58.3 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-methyl-5-oxopyrrolidin-1-yl)benzamide (80 mg) described in Example 837 and 1-methylpiperazine (52 mg) and by the reaction and treatment in the same manner as in Example 770, the title compound (37 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.CCOC(C)=O>[CH2:26]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:14]=2)[C:10]([CH:18]=[O:19])=[C:11]1[CH:15]([CH3:16])[CH3:17])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
General Procedure C. To a solution of ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 2.08 g, 8.04 mmol) in DMF (15 ml) was added K2CO3 (3.32 g, 24.1 mmol) and benzyl bromide (1.91 ml, 16.1 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→35% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH:30]2[CH2:36][C:37]([O:39][CH3:40])=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:23]([C:19]1[CH:18]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[N:22]=[CH:21][N:20]=1)=[O:24])[CH2:31][CH:30]2[CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: COC(=O)CC1CNc2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccc(F)cc21

Procedure:
150 mg (0.441 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 105 mg (0.500 mmol) methyl (5-fluoro-2,3-dihydro-1H-indol-3-yl)-acetate, 148 mg (0.460 mmol) TBTU and 112 μL (0.80 mmol) triethylamine in 2 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by preparative HPLC-MS without any further working up. The product fractions were combined and lyophilised.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:27])[NH:25][CH3:26])=[CH:20][CH:19]=2)[N:13]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].Br[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[F:49].O>CN(C=O)C>[Si:3]([O:10][C@H:11]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C@H:12]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24](=[O:27])[N:25]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[F:49])[CH3:26])=[CH:22][CH:23]=2)[N:13]1[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:5])[CH3:4]
Reactant: CNC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reactant: Fc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1F)C(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccccc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
NaH (6.1 mg of a 60 wt % dispersion in mineral oil, 0.153 mmol, 1 equivalent) was added to a stirred, room temperature mixture tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(phenyl)methyl]-5-[4-(methylcarbamoyl)benzyl]pyrrolidine-1-carboxylate (80 mg, 0.148 mmol) in DMF (0.74 mL), and the mixture was stirred for 10 minutes. 1-(Bromomethyl)-2-fluorobenzene (0.0281 mg, 0.148 mmol, 1 equivalent) was added and the mixture was stirred overnight. Water was then added and the mixture was partitioned with EtOAc. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by normal phase flash chromatography using silica gel (0-50% hexanes/ethyl acetate). The product was collected and concentrated in vacuo to afford the title compound (95 mg, 99%). LC-MS=669.2 (M+Na)+.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH:21]([CH:10]2[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: CC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(F)cc1F
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(Oc1ccc(Cl)cn1)C1CNCC1c1ccc(F)cc1F
Temperature: 100 °C
Yield: 78.3 %

Procedure:
To a solution of 2-{(RS)-1-[(3SR,4RS)-1-benzyl-4-(2,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 570 mg (1.32 mmol) dissolved in toluene (12 mL) were added 0.43 mL (3.96 mmol) of 1-chloroethyl chloroformate and 0.68 mL (3.96 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 350 mg (78%) of the title compound as a light yellow oil. ES-MS m/e: 339.1 (M+H+).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[Cl-].C(N(CC)CC)C.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=O.C(=O)(O)[O-].[Na+]>O>[Br:2][C:1]([Br:5])=[CH:19][C:15]1[O:14][CH:18]=[CH:17][CH:16]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccco1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: BrC(Br)=Cc1ccco1
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
To a stirred solution of 9.6 g (29 mmol) of carbon tetrabromide in 120 mL of dry me hylene chloride at 0° was added 15.2 g (58 mmol) of tripheiiylphosphine. After 15 min 3.0 mL (22.5 mmol) of triethylamine was added, and after stirring another 5 min at 0°, the reaction mixture was cooled to -780°. At this temperature 1.50 mL (22.5 mmol) of 2-furaldehyde was added quickly dropwise, and after addition was complete, the mixture was stirred a -70° for 30 min. The reaction mixture was poured onto a rapidly stirring saturated solution of sodium bicarbonate in water. The methylene chloride phase was removed and the aqueous layer was extracted with additional methylene chloride. The combined extracts were evaporated to a solid which was stirred in 500 mL of hexanes for 2 h. After filtration, the filtrate was concentrated to a volume of 50 mL and the filtered again to remove precipitated solid. Final evaporation of the filtrate afforded 3.1 g (58%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:28])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:28][C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:29])[C@H:18]3[CH3:30])=[CH:15][C:14]=1[NH:13][C:10]1([CH3:12])[CH2:9][NH:8][CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CNC4)cc3N21
Yield: 101.2 %

Procedure:
A solution of 3-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (Example #148, Step G, 5 g, 10.4 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at ambient temperature for 3 h. The solvent was removed in vacuo to give (R)-7-bromo-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.19 (s, 1H), 5.83 (s, 1H), 5.55 (s, 1H), 4.91 (q, J=6.4 Hz, 1H), 4.51 (s, 2H), 4.05 (m, 4H), 1.55 (s, 3H), 1.25 (d, J=6.4 Hz, 3H). LC/MS (Table 1, Method 6) Rt=0.656 min.; MS m/z: 380 [M+H]+ and 382 [M+H+2]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[C:6]3[C:12]([C:13]([F:16])([F:15])[F:14])=[N:11][N:10]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([C:4]2[C:5]([N:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]3)=[C:6]3[C:12]([C:13]([F:14])([F:16])[F:15])=[N:11][N:10]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[C:7]3=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(C(F)(F)F)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(C(F)(F)F)c3c(N4CCNCC4)c(C4CC4)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
tert-Butyl 4-(5-cyclopropyl-1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (270 mg, 0.5 mmol) was placed in DCM (8 mL) at room temperature. TFA (1.5 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The crude product was then azeotroped with toluene (3×) and then dried on a vac line for 1 hour to give the crude product 5-cyclopropyl-1-(4-methoxybenzyl)-4-(piperazin-1-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (0.2 g, 91% yield), which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[NH:5]C(=O)C.[ClH:22]>C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:22].[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([CH2:9][CH:4]([C:3]([OH:21])=[O:2])[NH2:5])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)C(CS(=O)(=O)c1ccc(OC)cc1)NC(C)=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)CC(N)C(=O)O)cc1

Procedure:
Part A: A solution of (18.13 g, 57 mmol) of N-acetyl-β-(4-methoxyphenylsulfonyl)-D,L-alanine methyl ester in 125 mL concentrated hydrochloric acid and 125 mL of glacial acetic acid was refluxed for several hours under nitrogen atmosphere. The contents were concentrated by rotory evaporation to yield a crude solid which was slurried in dry toluene and filtered to yield 14.3 g of β-(4-methoxyphenylsulfonyl)-D,L-alanine hydrochloride as a white crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Br[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])#[N:2]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc(C#N)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
A mixture of 5-cyanoindole (10 g) and freshly prepared silver carbonate on diatomaceous earth (40.66 g) was stirred and heated under reflux in toluene (100 ml) for 18 hr, under an atmosphere of nitrogen. The mixture was cooled to room temperature, methyl 4-bromomethyl-3-methoxybenzoate (22.7 g) added, and stirring continued for 4 hr. Ethyl acetate (200 ml) was added, the mixture filtered through diatomaceous earth, the filter pad washed with ethyl acetate and the filtrate evaporated. The dark oil obtained was purified by flash chromatography, eluting with 45:45:10 hexane:methylene chloride:ethyl acetate, to give a foam which was crystallized from toluene to give methyl 4-(5-cyanoindol-3-ylmethyl)-3-methoxybenzoate (11.8 g, 53%) as white crystals; mp 148°-149°; partial NMR (250 MHz, DMSO-d6): 3.83(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.08(s, 2H, ArCH2Ar'), 8.00(s, 1H, H4 -indole), 11.49(br s, 1H, H1 -indole).