Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=O)[CH:7]=1.[CH3:17][NH:18][NH2:19]>O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:18]([CH3:17])[N:19]=[C:8]2[C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1
Reactant: O=C(c1cncnc1)c1cc(Br)ccc1F
Reactant: CNN
Solvent: C1COCCO1
Product: Cn1nc(-c2cncnc2)c2cc(Br)ccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A heavy wall pressure flask was charged with (5-bromo-2-fluorophenyl)(pyrimidin-5-yl)methanone (2.08 g, 7.4 mmol) and dioxane (20 mL). Methylhydrazine (0.86 mL, 16.3 mmol) was then added, and the mixture was heated to 100° C. for 16 hours. The crude mixture was concentrated, and the residue suspended in DCM. After storing at −10° C. for 2 hours, the precipitated solids were filtered off to give the product. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 2H), 9.22 (s, 1H), 8.39 (d, J=1.1 Hz, 1H), 7.76 (d, J=8.9 Hz, 1H), 7.62 (dd, J=8.9, 1.7 Hz, 1H), 4.15 (s, 3H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:18]=1
Reactant: N#Cc1ccco1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2ccco2)sc2ccccc12
Yield: 18.9 %

Procedure:
A mixture of methyl thiosalicylate (1.01 g, 6.0 mmol), 2-furonitrile (0.57 g, 6.0 mmol), triethylamine (1.5 ml, 10.7 mmol) and toluene (20 ml) was refluxed for 24 hrs. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (0.26 g, 19%).
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CC(C)=O.O>[CH2:49]([O:48][C:46]([CH2:45][N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:15][C@H:16]1[C@@H:20]([NH:22][C:23]1[N:28]=[C:27]([N:29]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[N:31]=[CH:30]2)[CH:26]=[CH:25][N:24]=1)[CH3:21])=[O:47])[CH3:50]
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CN1CCN(C(=O)Nc2cccc3ccccc23)C[C@H]1[C@H](C)Nc1nccc(-n2cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.5 %

Procedure:
To a solution of 2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 26 mg) in 0.5 mL of acetone was added potassium carbonate (11 mg) and ethyl bromoacetate (13.2 mg). The solution was stirred for 48 hours at room temperature, then diluted with 0.5 mL of water and extracted with 3×0.5 mL of CH2Cl2. The combined organics were washed with 1 mL of brine, dried with Na2SO4, and concentrated. The residue was purified by preparative HPLC (60:40 95% H2O-5% TFA:95% CH3CN-5% TFA) followed by preparative thin-layer chromatography, eluting with 95:5 25 CHCl3-isopropanol to provide 8.7 mg of the title compound. Mass spectrum (ESI) 579.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[O:26][C:27]([CH3:34])([CH3:33])[C:28](=[O:32])[NH:29][C:30]=3[N:31]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[P:41]([O:53][CH2:54]Cl)([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C(=O)C.C(OC(C)C)(=O)C>[P:41]([O:53][CH2:54][N:29]1[C:28](=[O:32])[C:27]([CH3:34])([CH3:33])[O:26][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=4)[N:4]=3)=[N:31][C:30]1=2)([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:42]
Reactant: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)NC(=O)C(C)(C)O4)n2)cc(OC)c1OC
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(Nc2ncc(F)c(Nc3ccc4c(n3)N(COP(=O)(OC(C)(C)C)OC(C)(C)C)C(=O)C(C)(C)O4)n2)cc(OC)c1OC
Temperature: 40 °C

Procedure:
A mixture of 6-[[5-Fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step B) (382 kg, 1.00 mol eq), tetra-n-butylammonium chloride (57.5 kg, 0.25 mol eq) and potassium carbonate (252 kg, 2.25 mol eq) in N,N-dimethylacetamide (1792 kg) is warmed to about 40° C. with stirring. To this is added a solution of ditert-butyl chloromethyl phosphate (Example 2) in isopropyl acetate (229 kg ditert-butyl chloromethyl phosphate, 1.10 mol eq, about 25% w/v solution). The resulting mixture is stirred for about 8 hours and then cooled to about 5° C. Isopropyl acetate (1329 kg) is added and then water (2292 kg) slowly, maintaining the temperature at <25° C. The layers are then separated, retaining the upper layer of the three observed. To this is added acetic acid (99 kg) and the resulting solution of the sub-title compound is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C:15]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=2[F:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1ccc(F)cc1F
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 2,4-difluorophenol: 1H-NMR (CDCl3) δ 7.90 (1H, d, J=2.8 Hz), 7.39 (1H, dd, J=8.8, 2.8 Hz), 7.05–6.91 (2H, m), 6.89–6.80 (1H, m), 6.80 (1H, d, J=8.8 Hz), 3.85 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:21][NH:22][C:23]1[S:24][C:25]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:28][C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[S:10]([NH:9][C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([C:30]2[CH:29]=[CH:28][C:26]3[N:27]=[C:23]([NH:22][CH3:21])[S:24][C:25]=3[CH:31]=2)[CH:3]=1)(=[O:12])=[O:11]
Reactant: CNc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Nc1cc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CNc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4c(C)cccc4Cl)c3)cc2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
N-(5-bromo-2-chloropyridin-3-yl)-2-chloro-6-methylbenzenesulfonamide (210 mg, 0.530 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (101.6 mg, 0.350 mmol), potassium carbonate (250 mg, 1.81 mmol), and Pd(dppf) Cl2*DCM complex (62.6 mg, 0.0768 mmol) were suspended in DME (2.0 ml) and water (0.5) ml. The reaction flask was fit with a reflux condensor and placed in a preheated oil bath (100° C.) and stirred under nitrogen for 1 hour. The reaction was cooled to room temperature, and the aqueous phase was removed via pipette. The reaction was then concentrated and filtered through a silica gel plug with 5:1 to 3:1 DCM/2 N ammonia in MeOH. The filtrate was concentrated and purified on HPLC (10% to 100% MeCN/water with 0.1% TFA over 30 minutes) to afford 2-chloro-N-(2-chloro-5-(2-(methylamino)benzo[d]thiazol-6-yl)pyridin-3-yl)-6-methylbenzenesulfonamide (35.6 mg, 21% yield). MS (ESI pos. ion) m/z: 479 (MH+). Calc'd exact mass for C20H16Cl2N4O2S2: 478.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]2[CH:13]=[N:14][N:15]([C:16]3[N:21]=[C:20]([N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)[CH:19]=[CH:18][CH:17]=3)[C:9]=2[CH:8]=1>Cl.O1CCOCC1>[N:22]1([C:20]2[N:21]=[C:16]([N:15]3[C:9]4[CH:8]=[C:7]([C:2]5[CH:3]=[N:4][CH:5]=[CH:6][N:1]=5)[N:12]=[CH:11][C:10]=4[CH:13]=[N:14]3)[CH:17]=[CH:18][CH:19]=2)[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cnccn5)cc43)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(N2CCNCC2)nc(-n2ncc3cnc(-c4cnccn4)cc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.5 %

Procedure:
To a solution of tert-butyl 4-[6-(6-pyrazin-2-ylpyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate (30 mg, 0.065 mmol) in hydrogen chloride (4 mol/l) in 1,4-dioxane (1.5 ml, 6.0 mmol) and 1,4-dioxane; 1.5 mL was stirred at RT 18 h. The reaction was concentrated and submitted for reverse phase HPLC to give 144 (12 mg) in 34% yield. MS (ESI) m/z: 359.1. 1H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 9.65 (d, J=1.1 Hz, 1H), 9.34 (s, 1H), 8.78-8.74 (m, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.68 (d, J=5.3 Hz, 1H), 7.77 (t, J=8.1 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.67-3.61 (m, 4H), 2.97-2.90 (m, 4H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][O:24]C(=O)C)[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[O:28]C(=O)C(C)(C)C)[CH2:6]1)(=O)C.[OH-].[K+].C(O)(=O)C>C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH2:23][OH:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:35])[CH2:12][CH2:13][C@@H:14]2[OH:28])[CH2:6]1
Reactant: CC(=O)OC[C@]12CC[C@H](OC(C)=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)C(C)(C)C)CC[C@]12O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO)[C@@]1(O)CC[C@@H]2O
Temperature: 70 °C

Procedure:
A mixture of 30 mg of 3β ,19-diacetoxy-14β-hydroxy-17β-pivaloxy-5α-androstane and 3.0 ml of 0.2 N methanolic potassium hydroxide was heated at 70° C. for 16 hours under nitrogen whereupon the mixture was neutralized with 0.2 N glacial acetic acid in ethyl acetate and evaporated to dryness at reduced pressure. The residue obtained was treated with ethyl acetate and filtered through diatomaceous earth. Evaporation of the filtrate yielded 3β ,14β ,17β ,19-tetrahydroxy-5α-androstane as indicated by tlc analysis.
Reaction SMILES: C([NH:8][C:9]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[CH2:10]O)C1C=CC=CC=1.[CH3:18][C:19]([OH:21])=[O:20]>[Pd].CCO>[C:19]([O:21][CH2:10][C:9]([NH2:8])([CH2:15][O:16][CH3:17])[CH2:12][O:13][CH3:14])(=[O:20])[CH3:18]
Reactant: CC(=O)O
Reactant: COCC(CO)(COC)NCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COCC(N)(COC)COC(C)=O
Yield: 48.6 %

Procedure:
A mixture of crude 4-aza-3,3-bis-(methoxymethyl)-1-oxaspiro[4.5]decane (66A, 40.0 g, 0.174 mol) and 6N HCl (100 mL) was refluxed for 1 h. The mixture was cooled and washed with Et2O (3×100 mL). The volume of the aqueous layer was reduced to 25 mL by rotary evaporation, basified with excess 50% NaOH solution and extracted with a mixture of Et2O/CH2Cl2 (3:1, 2×200 mL). The organic layers were combined, the solvent removed and the resulting crude oil distilled to give 16.4 g (63.2%) of 2-amino-2,2-bis-(methoxymethyl)ethanol, (bp 109°-110°/15 mm). This material also contains some of the --NCH3 compound. This material was further purified by conversion to the --NCH2Ph derivative. Thus, a mixture of crude 2-amino-2,2-bis-(methoxymethyl)ethanol (15.0 g, ~0.10 mol), benzaldehyde (Aldrich, 7.42 g, 0.07 mol), NaBH3CN (Aldrich, 4.4 g, 0.07 mol) and CH3OH (100 mL) was stirred at 5° for 15 min then at RT for 2 h. H2O (50 mL) then excess 12N HCl was then added to the flask. The volume of the mixture was reduced to 50 mL by rotary evaporation. The mixture was washed with Et2O (100 mL), basified with 50% NaOH solution and extracted with Et2O (200 mL). After removal of the solvent the crude oil (15.54 g) was distilled to give 11.64 g of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol, bp 118°-119°/0.10 mm, shown to 99.7% pure by GLC (10% OV-17 on Chromasorb W at 250°), (C,H,N). A mixture of 2-benzylamino-2,2-bis-(methoxymethyl)ethanol (8.25 g, 0.0345 mol), 5% Pd/C (Aldrich, 1.0 g), abs. EtOH (250 mL) and glacial HOAc (25 mL) was hydrogenated in a Parr apparatus at 40 psi for 15 min. The catalyst was removed by filtration through a pad of Celite® and the solvent removed to give the crude product which after crystallization from abs. EtOH gave a 48.6% yield of 2-amino-2,2-bis-(methoxymethyl)ethanol acetate, mp 119.5°-120.5°, (C,H,N).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([O:17]C)[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.Br>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([OH:17])[C:10]([F:16])=[C:11]([F:15])[C:12]=3[F:14])[C:7](=[O:19])[C:6]([C:20]([OH:22])=[O:21])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: COc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(O)c2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
To 1.5 g of 1-cyclopropyl-6,7,8-trifluoro-1,4- dihydro-5-methoxy-4-oxo-3-quinolinecarboxylic acid was added 25 ml of hydrogen bromide in acetic acid (32%). The mixture was stirred at room temperature for 16 hours and concentrated to dryness. The residue was triturated with water:ethanol and filtered to give 1.15 g of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][S:9]([C:12]1[S:13][C:14]([CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2C3=NC=CC=C3N=C2)[CH:18]=1)(=[O:11])=[O:10])=[O:7])[CH2:2][CH2:3][CH3:4].B(Cl)(Cl)Cl.[N:41]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH2:45]CCC1.ClC(OCCCC)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][S:9]([C:12]1[S:13][C:14]([CH2:33][CH:34]([CH3:35])[CH3:36])=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[C:51]3[C:46](=[N:47][CH:48]=[CH:49][CH:50]=3)[N:41]=[CH:45]2)[CH:18]=1)(=[O:11])=[O:10])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2cnc3cccnc32)c1
Reactant: c1ccc(N2CCCC2)nc1
Agent: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2cnc3ncccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 3-(3-imidazo[4,5-b]pyridin-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (35.7 mg, 0.074 mmol; see Example 8(b)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (21.9 mg, 0.148 mmol) and butyl chloroformate (94.1 μL, 0.74 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound in 58% yield, over two steps, (22.8 mg, 0.043 mmol).
Reaction SMILES: [CH3:1][C:2]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:12][C:5]([C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[C:4]([N+:26]([O-])=O)[CH:3]=1>[C].[Pd].CO>[NH2:26][C:4]1[CH:3]=[C:2]([CH3:1])[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)=[CH:12][C:5]=1[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)c(C(=O)OC(C)C)cc1Oc1ccc(OC(F)(F)F)cc1
Yield: 95.1 %

Procedure:
An 80% methanol (225 g), 50 g of isopropyl 4-methyl-2-nitro-5-(4-(trifluoromethoxy)phenoxy)benzoate, and 2.5 g of a 5% palladium carbon were charged into a 500-ml stainless steel autoclave equipped with a stirring device and a thermometer, and a reaction was allowed to proceed under a hydrogen pressure of 0.5 MPa at 30° C. for 6 hr. After the replacement of the air in the autoclave with nitrogen, the reaction solution was filtered using 220 ml of methanol to remove the catalyst. The methanol solution thus obtained was concentrated under the reduced pressure, and 208 ml of water was added to the residue. The precipitated solid was collected by filtration and was dried to give isopropyl 2-amino-4-methyl-5-(4-(trifluoromethoxy)phenoxy)benzoate (43.96 g, yield: 95%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:48]3[CH2:49][CH2:50][CH:45]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH2:46][CH2:47]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: C1CCN(C2CCNCC2)C1
Product: Cc1ccccc1-c1nc(N2CCC(N3CCCC3)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 92.2 %

Procedure:
In a similar-manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with 4-(pyrrolidine-1-yl)piperidine (27.8 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyrrolidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine (89.5 mg, 92%).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:4][C:3]=1[O:19][CH3:20].C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:20][O:19][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:26]([OH:28])=[O:27]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1I
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Temperature: 0 °C
Yield: 48 %

Procedure:
A solution of 7.70 g (19.6 mmol) of 4-iodo-3-methoxy-5-methyl-3′-trifluoromethyl-biphenyl in 190 ml of THF was cooled down to −75° C.; then, 13.5 ml (21.6 mmol) of an n-butyl lithium solution (1.6 molar in n-hexane) was added slowly below −70° C. One hour later, the dark-brown reaction mixture was treated with an excess of carbon dioxide gas (dried by bubbling through H2SO4 conc. in a gas washing device) during 2 hours and then warmed up to 0° C. It was subsequently poured into crashed ice, the pH was then adjusted to 3-4 with HCl/H2O (1N) and the mixture was extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by re-crystallization from EtOAc/heptane to give 2.90 g (48%) of the title compound as colorless solid. MS: 309.3 (M−H−).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(C(C)=O)c1

Procedure:
1.0 eq. of methyl 3-acetyl-4-hydroxybenzoate was reacted with 1.1 eq. each of K2CO3 and benzyl bromide in absolute DMF to form methyl 3-acetyl-4-benzyloxybenzoate. Colorless crystals, mp 68°-72° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=2)(O)[CH2:8][CH2:7]1)=[O:5])C.S(=O)(=O)(O)O>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=2)=[N:14][CH:15]=1
Reactant: CCOC(=O)C1CCC(O)(c2ccc(Cl)cn2)CC1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C1CC=C(c2ccc(Cl)cn2)CC1
Temperature: 60 °C

Procedure:
A mixture of 4-(5-chloropyridin-2-yl)-4-hydroxycyclohexanecarboxylic acid ethyl ester (1.6 g) and sulfuric acid (5 ml) is heated at 60° C. for 15 minutes. After addition of water (0.4 ml) the mixture is again heated at 60° C. for 20 minutes. The cooled reaction mixture was diluted with water and washed with dichloromethane. The aqueous phase was adjusted to pH 7 with sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over sodium sulfate and concentrated. The product with the molecular weight of 237.69 (C12H12ClNO2); MS (ESI): 238 (M+H+) was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH:16]=[O:17])[NH:8]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]([CH:16]=[O:17])[NH2:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN(C=O)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NN(C=O)Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of tert-butyl 2-(4-fluorobenzyl)-2-formylhydrazinecarboxylate (0.11 g, 0.410 mmol, 1.0 equiv) in CH2Cl2 (1.02 mL) was added TFA (1.02 mL). Gas evolution was observed. After stirring 30 min, the reaction was poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo to provide the title compound (0.056 g, 81% yield) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm (first tautomer) 8.24 (s, 1H), 7.18-7.31 (m, 2H), 7.00-7.14 (m, 2H), 4.47 (s, 2H), 4.11 (s, 2H), (second tautomer) 8.37 (s, 1H), 7.18-7.31 (m, 2H), 7.00-7.13 (m, 2H), 4.62 (s, 2H), 3.63 (s, 2H); LCMS (ES+, (M+H)+) m/z 169.27.
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:48])[NH:15][CH:16]([C:21]([N:23]1[CH2:27][CH2:26][CH:25]2[N:28]([C:42](=[O:47])[NH:43][CH:44]([CH3:46])[CH3:45])[CH2:29][CH:30]([O:31][C:32](=[O:41])[NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:24]12)=[O:22])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])C)C1C=CC=CC=1>CO>[CH3:20][C:17]([CH3:18])([CH3:19])[CH:16]([NH:15][C:14](=[O:48])[CH:12]([NH:10][CH3:9])[CH3:13])[C:21]([N:23]1[CH:24]2[CH:25]([N:28]([C:42](=[O:47])[NH:43][CH:44]([CH3:46])[CH3:45])[CH2:29][CH:30]2[O:31][C:32](=[O:41])[NH:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:26][CH2:27]1)=[O:22]
Reactant: CC(C)NC(=O)N1CC(OC(=O)NCc2ccccc2)C2C1CCN2C(=O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: CO
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(OC(=O)NCc1ccccc1)CN2C(=O)NC(C)C)C(C)(C)C
Reaction time: 3.5 h
Yield: 64.5 %

Procedure:
A mixture of 58 (250 mg, 0.37 mmol) and 10% Pd-on-carbon (wet, 100 mg, 0.10 mmol) in MeOH (10 mL) was stirred vigorously under an atmosphere of H2. After 3.5 h, the catalyst was removed by filtration with an Acrodisc® 0.45 μm nylon membrane syringe filter and the solvent was removed in vacuo. The crude product was purified by reverse-phase HPLC (2″ Dynamax® C18, 20-80% MeOH/water containing 0.1% HOAc over 25 min; Flow: 40 mL/min). The product-containing fractions were combined and lyophilized to provide 59 (130 mg, 65%) as a flocculent white powder.