Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26](S(C)(=O)=O)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1[C:22](=[O:44])[C:23]2[CH:28]=[N:27][C:26]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[N:25][C:24]=2[N:33]([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[CH2:40][CH2:39][CH2:38]3)[CH:34]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: Nc1ccc(CCN2CCOCC2)cc1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(CCN4CCOCC4)cc3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 4-(2-morpholin-4-yl-ethyl)-phenylamine (49 mg, 0.24 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 100 mg, 0.24 mmol). The title compound was obtained as a yellow solid (60 mg, 46%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (s, 1H), 8.45 (s, 1H), 7.50 (br, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.21 (m, 3H), 7.13 (d, J=7.8 Hz, 1H), 6.87 (br, 2H), 4.31 (q, J=7.0 Hz, 2H), 3.69 (br, 4H), 2.96 (t, J=7.4 Hz, 2H), 2.91 (t, J=7.4 Hz, 2H), 2.67 (br, 2H), 2.46 (br, 6H), 2.17 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@@H:6]1[CH2:11][O:10][C:9]2=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]2[CH2:7]1)=[O:4].[F:18][C:19]([F:38])([F:37])[O:20][C:21]1[CH:36]=[CH:35][C:24]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1>>[F:38][C:19]([F:18])([F:37])[O:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH2:2][C:3]([NH:5][C@@H:6]3[CH2:11][O:10][C:9]4=[N:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][N:8]4[CH2:7]3)=[O:4])[CH2:28][CH2:27]2)=[CH:35][CH:36]=1
Reactant: O=C(CCl)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Reactant: OCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Product: O=C(COCCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Yield: 47.2 %

Procedure:
Similar to the manipulation of example 1, with (S)-2-chloro-N-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yl)acetamide (130 mg, 0.50 mmol) and 2-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)ethanol (305 mg, 1.0 mmol) as crude materials, 125 mg title compound was generated and yield was 47%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[C@H:15]([CH2:20][CH2:21][S:22][CH3:23])[NH:16][C:17](=[O:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C@H:15]([C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:24])[CH2:20][CH2:21][S:22][CH3:23])(=[O:19])[CH3:18]
Reactant: CSCC[C@H](NC(C)=O)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(C)=O)C(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.7 %

Procedure:
To a solution of 8.6 g (0.024 mol) of 1-(t-butoxycarbonyl)-4(N-acetyl-L-methionyl)piperazine in 60 ml of dichloromethane was added 10 ml of trifluoroacetic acid and the mixture was stirred at room temperature overnight. The solution was extracted with water and the resulting aqueous solution was made basic with sodium hydroxide. The product was extracted with dichloromethane, dried over sodium sulfate, and filtered. Evaporation of the solvent gave 2.1 g of 1-(N-acetyl-L-methionyl)piperazine, as an oil: IR (film) 3304, 3051, 2917, 2861, 1645, 1546, 1448, 1377 cm-1 ; NMR (CDCl3) δ 1.95 (m, 2 H), 2.02 (s, 3 H), 2.10 (s, 3 H), 2.54 (m, 2 H), 2.98 (m, 4 H), 3.74 (m, 4 H), 5.10 (m, 1 H), 6.40 (b, 0.5 H), 6.48 (b, 0.5 H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[F:26])[CH3:9])(C)(C)C.Cl>C(Cl)(Cl)Cl>[Br:18][C:15]1[CH:16]=[CH:17][C:12]2[NH:11][C:10](=[O:28])[CH:8]([CH3:9])[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:13]=2[CH:14]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cc1C(=O)c1ccccc1F
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC1N=C(c2ccccc2F)c2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.4 %

Procedure:
To a stirred solution of the benzophenone 136 (30 g, 64.4 mmol) in CHCl3 (300 mL) at rt, hydrogen chloride gas was added slowly. After 20 min, the addition was stopped and the solution was allowed to stir overnight at rt. The reaction mixture was then washed with a saturated solution of sodium bicarbonate (2×70 mL) and water (2×70 mL). The organic layer was concentrated under reduced pressure. The residual oil was dissolved in methanol-water (1:1, 300 mL) and the pH was adjusted to 8.5 by the addition of aq sodium hydroxide (1 N). The reaction mixture was allowed to stir for 10 h at rt. The solution was then concentrated under reduced pressure and water (100 mL) was added. The solution was extracted with CH2Cl2 (3×50 mL), and the organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude solid 137 was purified by recrystallization from methanol/water to provided 137 (18.2 g, 82%). mp 183-185° C.; IR (KBr, cm−1) 2928, 1694, 1611, 1479, 1450, 1377, 1315; 1H NMR (CDCl3) δ 9.50 (bs, 1 H), 7.62-7.65 (m, 2 H), 7.50 (q, J=6.5 Hz, 1H), 7.40 (d, J=2.0 Hz, 1 H), 7.29 (t, J=7.5 Hz 1 H) 7.15 (d, J=8.6 Hz, 1 H), 7.11 (t, J=8.9 Hz, 1 H), 3.84 (q, J=6.5 Hz, 1 H), 1.82 (d, J=6.5 Hz, 3 H); MS (EI) m/e (relative intensity) 348 (M++1, 23), 347 (M+, 38), 346 (24), 345 (36), 329 (19), 327 (20), 307 (40), 306 (41), 305(100), 304 (37), 303 (63); [α]26D=−169.1 (c 0.71, EtOAc).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Cl)[CH:21]=1)=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2].[CH2:27]([S:29](C1C=CC(S)=CC=1)(=[O:31])=[O:30])[CH3:28]>>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19][C:20]1[CH:25]=[CH:24][C:23]([S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])=[CH:22][CH:21]=1)=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1c(Sc1cccc(Cl)c1)c(C)n2CC(=O)O
Reactant: CCS(=O)(=O)c1ccc(S)cc1
Product: CCS(=O)(=O)c1ccc(Sc2c(C)n(CC(=O)O)c3cccc(NC(C)=O)c23)cc1

Procedure:
The title compound was prepared by the method of Example 5 part (iv) using the product from Example 17 part (i) and 4-(ethylsulfonyl)benzenethiol. The product was purified by preparative hplc (eluent MeCN/NH3 (aq)).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[C:22]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:43])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[N:37]3)[CH2:30][CH2:29]2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[Cl:27][C:25]1[CH:26]=[C:21]([NH:20][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=2)[C:22]([N:28]2[CH2:33][CH2:32][N:31]([C:34](=[O:43])[CH2:35][N:36]3[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[N:37]3)[CH2:30][CH2:29]2)=[N:23][CH:24]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3N)CC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)n(CC(=O)N2CCN(c3ncc(Cl)cc3NC(=O)c3ccc(S(C)(=O)=O)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 4-methanesulfonyl-benzoic acid (0.030 g, (0.150 mmol) in methylene chloride (2 mL) is added oxalyl chloride (0.017 mL, 0.200 mmol) followed by 1 drop of N,N-dimethylformamide. Vigourous bubbling is observed and the reaction mixture is stirred at room temperature for 2 h. The mixture is concentrated under a stream of nitrogen. The residue is dissolved in methylene chloride (2 mL) and 1-[4-(3-amino-5-chloro-pyridin-2-yl)-piperazin-1-yl]-2-(3,5-dimethyl-pyrazol-1-yl)-ethanone (0.040 g, 0.110 mmol) is added followed by (0.040 mL, 0.220 mmol) N,N-diisopropylethylamine (0.040 mL, 0.220 mmol). The mixture is stirred at room temperature for 3 days then concentrated under a stream of nitrogen. The residue is dissolved in dimethylsulfoxide and purified by reverse phase preparative HPLC to provide, after removal of the eluent, 0.022 g of N-(5-Chloro-2-{4-[2-(3,5-dimethyl-pyrazol-1-yl)-acetyl]-piperazin-1-yl}-pyridin-3-yl)-4-methanesulfonyl-benzamide as a white solid in 36% yield. MS; MH+=531.8
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:17][CH2:18][CH:19]=O)[C:10]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:29]=[CH:28][C:27]([C@:30]23[CH2:35][C@H:34]2[CH2:33][NH:32][CH2:31]3)=[CH:26][CH:25]=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.O>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][C@H:34]3[C@:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:37])[F:36])=[CH:29][CH:28]=4)([CH2:35]3)[CH2:31]2)[C:10]1=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=CCCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 3-(3-benzoyl-5-iodo-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-propionaldehyde (Prep 38, 700 mg, 1.7 mmol) in dichloromethane (20 mL), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep 4, 399 mg, 1.7 mmol), AcOH (158 mg, 2.5 mmol) and NaBH(AcO)3 (410 mg, 1.9 mmol) were added at 0° C. The mixture was stirred at 0° C. for further 1 hours. Water was added and the solvent was evaporated under vacuum, the residue re-dissolved in ethyl acetate and the mixture washed with a 5% solution of aqueous NaHCO3. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (97-3-1) to give the title compound as a white solid (880 mg, 83% yield).
Reaction SMILES: C(OC(C)C)(=O)C.[F:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([C:22]([OH:24])=O)[CH2:13][C:12]2=1.[OH-].[NH4+:26].C(Cl)(=O)C(Cl)=O>O.CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([C:22]([NH2:26])=[O:24])[CH2:13][C:12]2=1
Reactant: [NH4+]
Reactant: O=C(O)C1CCc2[nH]c3ccc(F)cc3c2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Isopropyl acetate (570 mL, 488 g) was charged to a (3-L) four-necked reactor (reactor A) equipped with mechanical stirrer, condenser with nitrogen inlet, powder addition funnel, and a thermocouple. 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (Example 90) was charged to the reactor with stirring. The reaction mixture was cooled to 5-10° C. with an ice-bath and DMF (13.8 g) was added. Ammonium hydroxide (28% aqueous, 607 g) and water (144 g) were added to another (5-L), 4-neck reactor (reactor B) equipped with an overhead stirrer, thermocouple, and condenser under nitrogen. The contents of reactor B were cooled 5-10° C. Reactor B was connected to a caustic scrubber. Oxalyl chloride (94.3 g, 0.74 mol) was added through an addition funnel to the stirring slurry in reactor A maintaining temperature between 5 and 15° C. The funnel was rinsed with 50 mL of isopropyl acetate and the reaction mixture was allowed to warm to 10-15° C. The reaction mixture was stirred for an additional 30 min after addition of oxalyl chloride and an aliquot (3 drops) of the reaction mixture was quenched with 0.11 mL of 28% aq. ammonium hydroxide then diluted with CH3CN to 2 mL, and monitored for disappearance of the acid by HPLC (<10-11 area % of the acid). When the reaction was complete, the contents of reactor A were cooled to 5-10° C. The acid chloride from reactor A was transferred to the cooled ammonium hydroxide solution in reactor B over 30 min to 45 min maintaining temperature between 5-15° C. followed by a 50 mL isopropyl acetate rinse. The reaction mixture was stirred at 5-10° C. for 30 min when solids separated out. Heptane (540 mL) was charged at 10-15° C. and stirring continued for 30 min. The slurry was filtered through a funnel lined with polypropylene and the collected solid washed with 800 mL of cold water followed by 800 mL of n-heptane. The solid was dried under vacuum (<20 mm Hg) at 40° C. to give 140.4 g of 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide (94% yield). Chiral purity is 99.4% by HPLC and MW 232(LC/MS).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH:20]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[CH:21]([N:24]([CH3:26])[CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:25][N:24]([CH3:26])[CH:21]([CH2:22][CH3:23])[CH:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[S:12][C:13]=2[CH:19]=1)[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCC(C(c1ccc2nc(Oc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(c1ccc2nc(Oc3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)oxy)benz oate (65 mg, 0.14 mmol) and lithium hydroxide monohydrate (30 mg, 0.72 mmol) in 4 mL of dioxane and 2 mL of water was heated together with stirring at 50° C. for 4 hr. The mixture was concentrated in vacuo and the residue dissolved in about 2 mL of water. The solution was neutralized with 1N HCl then concentrated again in vacuo. The residue was purified by PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to give the title compound. MS (ESI+) m/z 437.21 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)([N:14]1C=CN=C1)=O.N>CN(C=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:9]([NH2:14])=[O:11])[NH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1cc([N+](=O)[O-])n[nH]1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of 5-nitro-3-pyrazolecarboxylic acid (6.28 mg, 40 mmol) in DMF (30 mL) was added carbonyldiimidazole (12.96 mg, 80 mmol) The mixture was allowed to stir for 30 min, and ammonia in MeOH (2M, 60 mL) was added. The reaction mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure to afford the crude product which was then washed with ether to afford 3-nitro-1H-pyrazole-5-carboxamide (3.0 g, 48%), which was used directly in the next step without further purification. LC-MS (ESI) m/z 155 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:1][C:2]1[C:3]([N:24]([CH2:25][CH2:26][OH:27])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CNCCO
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 22.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and 2-methylamino-ethanol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.57 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=434.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([OH:31])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH2:32]1[O:34][C@@H:33]1[CH2:35][OH:36].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:19]3[C:26]4[CH:27]=[CH:28][C:29]([O:31][CH2:32][C@H:33]([OH:34])[CH2:35][OH:36])=[CH:30][C:25]=4[S:24][C:20]=3[N:21]=[CH:22][N:23]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: OC[C@@H]1CO1
Reactant: Oc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@@H](O)COc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
To a solution of 4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-ol (30 mg, 0.07 mmol) in EtOH (1.0 mL) was added (R)-(+)-glycidol (5 mg, 0.07 mL, 1.0 equiv) and triethylamine (0.34 mg, 0.0035 mmol, 0.05 equiv) under nitrogen. The reaction mixture was stirred at 80° C. for 15 h and then cooled to rt. The solvents were removed in vacuo. The residue was purified by preparative HPLC to afford (2R)-3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)[1]benzothieno[2,3-d]pyrimidin-7-yl]oxy}propane-1,2-diol as a white solid (14.8 mg, 40%). 1H-NMR (CD3OD) δ 8.45 (s, 1H), 8.32 (d, J=8.9 Hz, 1H), 7.73 (d, J=2.7 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.46 (dd, J=2.7, 9.0 Hz, 1H), 7.40 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.25 (dd, J=2.3, 9.0 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.05 (td, 1H), 5.22 (s, 2H), 4.20 (m, 1H), 4.11 (m, 1H), 4.04 (m, 1H), 3.72 (m, 2H), LCMS RT=3.32 min, [M+H]+=526.1.
Reaction SMILES: [O-]CC.[Na+].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]>C(O)C.O1CCCC1>[CH2:22]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCCCBr
Reactant: OCCc1ccc(O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCCCCCCOc1ccc(CCO)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Sodium ethoxide (4.98 g) was added to a solution (240 ml) of 2-(4-hydroxyphenyl)ethyl alcohol (8.68 g) in absolute ethanol and the mixture was stirred at 50° C. for 30 minutes. A solution of 7-octenyl bromide (10 g) in anhydrous tetrahydrofuran was dropwise added thereto and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was concentrated, poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away and the residue was purified by silica gel chromatography (eluent; ethyl acetate:hexane=1:5) to give the subject compound (10.76 g) as an oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][N:40]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:39][CH2:38]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(Cc2ccc(NC(=O)C3=Cc4cc(-c5ccc(C)cc5)ccc4CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 67.5 %

Procedure:
In DMF (3ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150mg), and to the solution were added 1-(2-methoxyphenyl)piperazine (97mg) and potassium carbonate (268mg). The mixture was stirred at room temperature for 13 hours, and to the mixture was added water (50ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give N-[4-[1-(2-methoxyphenyl)-4-piperazinylmethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 41) (142mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH:16]=1.O1CCCC1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])O.[Na+]>O.ClCCl>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]([F:15])([F:13])[F:14])=[CH:7][C:6]=2[CH:16]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2oc(CCC(F)(F)F)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ccc2oc(CCC(F)(F)F)cc2c1
Yield: 95.4 %

Procedure:
A solution of 2.0 g (8.7 mmol) of 5-amino-2-(3,3,3-trifluoropropyl) benzofuran in 30 ml of a 9/1 mixture of tetrahydrofuran and water is reacted for 30 min with 0.92 ml (9.6 mmol) of ethyl chloroformate in the presence of 1.1 g (13 mmol) of sodium hydrogen-carbonate. The reaction mixture is then diluted with water and dichloromethane, and then the organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. 2.5 g of product are obtained. Melting point: 108° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.CCCP(=O)=O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:18]1([C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[O:24])=[CH:14][N:13]3[N:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Yield: 35.1 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (112 mg, 309 μmol), pyrrolidine (220 mg, 256 μl, 3.09 mmol), propylphosphonic anhydride in ethyl acetate 50% (492 mg, 455 μl, 773 μmol) and N,N-diisopropylethylamine (120 mg, 158 μl, 927 μmol) in tetrahydrofuran (7.00 ml) was refluxed for 18 hours. The solvent was evaporated, the residue was triturated with saturated aqueous sodium hydrogencarbonate. The precipitated solid was filtered off, washed with water and dried in vacuo, affording 2-methyl-4-(pyrrolidine-1-carbonyl)-2H-pyrazole-3-carboxylic acid (2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-amide (45 mg, 35%) as brown solid. Mp.: 210° C. MS: m/z=416.1 (M+H+).