Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:30]=[C:31]=[O:32].N[C:34]1[C:43]2[NH:42][C:41](=[O:44])[CH2:40][O:39][C:38]=2[CH:37]=[CH:36][CH:35]=1>CCOC(C)=O.CN(C=O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:31]([NH:30][C:34]2[C:43]3[NH:42][C:41](=[O:44])[CH2:40][O:39][C:38]=3[CH:37]=[CH:36][CH:35]=2)=[O:32])=[C:5]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: [N-]=C=O
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCC1
Reactant: Nc1cccc2c1NC(=O)CO2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2cccc(NC(=O)NCc3ccc(C(F)(F)F)cc3N3CCCC3)c2N1
Temperature: 80 °C
Yield: 21 %

Procedure:
Amine 2b (471 mg, 1.94 mmol) (Scheme 7) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (576 mg, 1.94 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 5 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1e (213 mg, 1.3 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 120 mg of a white solid. Yield=21% 1HNMR (DMSO, 400 MHz) δ 1.91 (4H, m), 3.21 (4H, m), 4.48 (2H, d, J=6 Hz), 4.63 (2H, s), 6.64 (2H, dd, J=10.8 Hz, J′=8 Hz), 6.88 (1H, t, J=8 Hz), 7.12 (1H, s), 7.19 (1H, d, J=8.8 Hz), 7.34 (1H, d, J=8 Hz), 8.63 (1H, t), 10.68 (1H, bs), 10.90 (1H, bs); [M+1] 435.2 (C21H21F3N4O3 requires 434.4).
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[N:4][C:5]([NH:8][CH:9]=[C:10]([C:16](OCC)=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:7]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[NH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]2=[O:17]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(-c2ccncc2)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(-c3ccncc3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A suspension of diethyl N-[3-fluoro-2-(4-pyridyl)-6-pyridyl]aminomethylenemalonate (11.5 g) in 120 ml of Dowtherm A was heated to reflux for 10 minutes and then cooled to room temperature. The resulting solid was filtered off. The filtrate was heated to reflux for 10 minutes and the solid was collected. The combined solid was washed successively with ethanol and ether to give ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-pyridyl)-1,8-naphthyridine-3-carboxylate (7.2 g, m.p. 280°-285° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([C:11]3[N:12]=[C:13]([NH2:16])[S:14][CH:15]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[CH:39]=[CH:38][NH:37][C:34]3=[N:35][CH:36]=2)O1>>[O:20]1[CH2:21][CH2:22][N:17]([C:4]2[C:5]3[S:10][C:9]([C:11]4[N:12]=[C:13]([NH2:16])[S:14][CH:15]=4)=[CH:8][C:6]=3[N:7]=[C:2]([C:31]3[CH:32]=[C:33]4[CH:39]=[CH:38][NH:37][C:34]4=[N:35][CH:36]=3)[N:3]=2)[CH2:18][CH2:19]1
Reactant: Nc1nc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cs1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: Nc1nc(-c2cc3nc(-c4cnc5[nH]ccc5c4)nc(N4CCOCC4)c3s2)cs1

Procedure:
4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)thiazol-2-amine was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure B to give, after purification by reverse HPLC, 41 mg of 429. MS (Q1) 436 (M+)
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([N:18]([CH3:20])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:22])[CH:8]=2)[N:3]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[O:42]([CH:44]([CH3:46])[CH3:45])[Na].C[O-].[Na+]>CC(O)C.CO>[CH3:19][N:18]([CH3:20])[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([C:29]3[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[OH:22])[CH:8]=2)[N:3]=[C:2]([O:42][CH:44]([CH3:46])[CH3:45])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]
Reactant: CC(C)O[Na]
Reactant: CN(C)c1c(-c2ccccc2)c(Cl)nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1nc2ccc(C(O)(c3ccncc3)c3cncn3C)cc2c(N(C)C)c1-c1ccccc1

Procedure:
The title compound was prepared using (2-chloro-4-(dimethylamino)-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanol (Example 47) and NaOiPr in iPrOH in place of (3-chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(pyridin-3-yl)methanol and NaOMe in MeOH, respectively, according to the procedure described in Example 79. 1H NMR (400 MHz, MeOH-d4) δ 9.08 (s, 1H), 8.84 (d, J=6.11 Hz, 2H), 8.11 (s, 1H), 8.05 (d, J=6.11 Hz, 2H), 7.87 (d, J=8.80 Hz, 1H), 7.64 (d, J=8.80 Hz, 1H), 7.33-7.50 (m, 3H), 7.16-7.27 (m, 3H), 5.32-5.50 (m, 1H), 3.72 (s, 3H), 2.59 (s, 6H), 1.23 (d, J=6.11 Hz, 6H); MS m/e 494.2 [M+H]+.
Reaction SMILES: [N:1]12[CH2:7][C:4]([C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:22]1([CH2:28][O:29][CH2:30][CH2:31][Br:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[Br-:32].[OH:9][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]12[CH2:7][N+:1]([CH2:31][CH2:30][O:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: BrCCOCc1ccccc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)C2
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOCc3ccccc3)(CC1)C2
Product: [Br-]
Temperature: 60 °C
Yield: 36 %

Procedure:
To a solution of 1-azabicyclo[2.2.1]hept-4-yl(diphenyl)methanol (50 mg, 0.18 mmol) in 2 CH3CN/3 CHCl3 (4 mL) was added 2-bromoethyl phenylmethyl ether (0.04 mL, 0.25 mmol). The solution was heated at 60° C. for 16 h, cooled down to room temperature and the solvents evaporated under vacuum. The residue was taken up in 2.5 mL of DMSO and purified by preparatory HPLC (without TFA) to give the title compound (32 mg, 36%). EI-MS m/z 414 (M+) Rt (1.92 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]2=[N:11][N:12]([CH3:22])[C:13]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[C:9]2[N:8]=[C:7]([CH3:23])[N:6]=1.CN1CC[O:28]CC1.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37](CC(O)=O)=[CH:36][C:35]=1[O:44][CH3:45])[CH3:32].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>CN(C)C(=O)C.CCOC(C)=O>[Cl:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:21])[C:14]=1[C:13]1[N:12]([CH3:22])[N:11]=[C:10]2[C:9]=1[N:8]=[C:7]([CH3:23])[N:6]=[C:5]2[NH:4][CH:3]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:31][CH3:32])=[C:35]([O:44][CH3:45])[CH:36]=1)[C:2]([NH2:1])=[O:28]
Reactant: CCOc1ccc(CC(=O)O)cc1OC
Reactant: Cc1nc(NCCN)c2nn(C)c(-c3c(Cl)cccc3Cl)c2n1
Reactant: CN1CCOCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOc1ccc(C(Nc2nc(C)nc3c(-c4c(Cl)cccc4Cl)n(C)nc23)C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of (2-aminoethyl)[3-(2,6-dichlorophenyl)-2,5-dimethylpyrazolo[3,4-e]pyrimidin-7-yl]amine (175 mg, 0.5 mmol) in N,N-dimethylacetamide (5 mL), add 4-methylmorpholine (101 mg, 1.0 mmol), 2-(4-ethoxy-3-methoxyphenyl)acetic acid (115 mg, 0.55 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (331 mg, 0.75 mmol). Stir the reaction mixture at ambient temperature for 14 h and dilute with EtOAc (15 mL). Wash the organic extracts successively with water (10 mL), brine (10 mL), saturated NH4Cl (10 mL), 2N NaOH (10 mL), brine (10 mL), dry over MgSO4 and evaporate under reduced pressure to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[O:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])C2=CC=CC=C2C1=O)=[O:5])[CH3:2].[OH2:47].NN>C(O)C>[C:39]([O:20][C:19]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[C:31]2[CH:43]=[CH:44][CH:45]=[CH:46][C:30]=2[O:29][CH2:28]1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:47])([CH3:42])([CH3:41])[CH3:40]
Reactant: O
Reactant: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: NN
Solvent: CCO
Product: CCOC(=O)[C@H](CCCCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 8 h
Yield: 159.7 %

Procedure:
A mixture of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.46 g), hydrazine hydrate (0.18 g) and ethanol (10 ml) is allowed to stand overnight at room temperature. The mixture is concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (50 ml×4). Water (50 ml) and sodium bicarbonate (0.5 g) are added to the organic extract, and to the resulting mixture is added dropwise di-tert-butyl dicarbonate (0.24 g) with stirring. After stirring for 30 minutes at room temperature, the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluent to yield tert-butyl 3(S)-[9-tert-butoxycarbonylamino-1(S)-ethoxycarbonylnonyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:25]>C1C=CC=CC=1>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:8]([Cl:25])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)O)cc1Oc1ccc(F)cc1F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 110.7 %

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-methanesulfonamidobenzoic acid (0.6 g) and phosphorus pentachloride (0.4 g) in benzene (6 ml) was warmed, dissolved, and then stirred for 25 minutes at room temperature. The mixture was concentrated under reduced pressure to give a powder of 3-(2,4-difluorophenoxy)-4-methanesulfonamidobenzoyl chloride (0.7 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9]1)C1C=CC=CC=1.[H][H].C([OH:30])C>C(O)(=O)C.[Pd]>[C:14]([OH:15])(=[O:30])[CH3:10].[C:22]1([CH3:25])[CH:21]=[CH:20][C:19]([S:16]([O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)OCC2CNCCO2)cc1

Procedure:
A solution of 4-benzyl-2-toluene-p-sulphonyloxymethylmorpholine (18.75 g.) in glacial acetic acid (50 ml.) is shaken in an atmosphere of hydrogen with palladium on carbon catalyst (0.5 g.; 5%) until no more hydrogen is absorbed (ca. 1.1 1.). The catalyst is then removed by filtration and the filtrate is evaporated under reduced pressure to give a colourless syrup which, on addition of ethanol, solidifies. Crystallisation from ethanol gives 2-toluene-p-sulphonyloxymethylmorpholine acetate, m.p. 140°-142° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[N:7]([CH3:20])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O)[CH3:2].C(N(CC)CC)C.SCC(O)=O>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[NH:7][CH3:20])[CH3:2]
Reactant: CCOC(=O)C[C@@H](c1ccc(OC)nc1)N(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CS
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C[C@H](NC)c1ccc(OC)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of sulfonamide 16-7 (4.7 gm, 10 mmol) in CH2Cl2 (50 mL) was treated with triethylamine (2.8 mL, 20 mmol) and mercaptoacetic acid (1.04 mL, 15 mmol). The reaction was stirred for 90 min at room temperature. The green solution was diluted with EtOAc (500 mL) and washed with satd aq NaHCO3 (150 mL), water (3×100 mL), and brine (3×100 mL). The solution was dried over Na2SO4, filtered and concentrated to a black oil. The residue was purified by flash chromatography (5% MeOH/CH2Cl2) to give the desired product 16-8.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)(Cl)Cl.ClCCl>[Cl:24][CH2:25][C:26]([N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 2 h
Yield: 37.1 %

Procedure:
A solution of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.4 g, 20 mmol), triethylamine (2.1 g, 21 mmol) in chloroform (50 ml) was added to a solution of chloroacetyl chloride (2.5 g, 22 mmol) in chloroform (100 ml) dropwise at room temperature. The mixture was stirred for 2 hours. The solution was diluted with dichloromethane (DCM, 100 ml) and then washed with H2O and brine. The solvent was removed and the oily product was purified by flash chromatography (SiO2, 50 g; eluted with DCM and 1% CH3OH in DCM). The pure product was obtained as an oil, 4.2 g. Crystallization from ethanol yielded 2.2 g of white crystals, m.p. 101°-102° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)N(C2CC2)CCC3(C)C)=[CH:7][CH:6]=1)[CH3:2].[CH2:29]([O:31][C:32](=O)[C:33]1[CH:38]=CC(I)=CC=1)C>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:31][C:32]1([C:20]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:28])=[CH:6][CH:7]=3)=[CH:22][CH:21]=2)[CH2:33][CH2:38]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 100.0 mg, 0.47 mmol) and ethyl-4-iodo benzoate (Reagent A, 141.0 mg, 0.51 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (109 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded 135.0 mg (90%) of the title compound as an orange solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=O)=[O:7])(C)(C)C.B.C1COCC1.[H-].[Na+]>C1COCC1>[O:7]=[C:6]1[N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:10][CH:9]2[CH2:21][O:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
1,4-Di(tert-butoxycarbonyl)piperazine-2-carboxylic acid (14.45 g, 43.7 mmol) was dissolved in THF (200 mL), and borane-THF complex (1.0 M solution in THF, 100 mL, 100 mmol) was added slowly. Upon complete addition, the reaction mixture was heated to 50° C. After 2 h, the reaction mixture was allowed to cool to rt and was slowly quenched by the dropwise addition of MeOH (50 mL). After gas evolution ceased, the reaction mixture was heated to 50° C. for 1 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The material was dissolved in THF (200 mL) and NaH (60% dispersion in mineral oil, 1.75 g, 43.7 mmol) was added portion wise. The reaction mixture was heated to 50° C. overnight. Upon cooling to rt, the reaction mixture was quenched with H2O (300 mL) and extracted with EtOAc (3×400 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified by column chromatography (10 to 40% EtOAc in Hexanes gradient) to give 6.31 g (59%) of the desired product as a white solid. Rf=0.43 in 80% EtOAc in Hexanes. 1.10 g (8%) of di-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate was also isolated. Rf=0.63 in 80% EtOAc in Hexanes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1)#[N:2].N1(CC2C=CN=CC=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].OS(O)(=O)=O>O.CO>[OH:10][CH2:9][C:5]1[CH:4]=[C:3]([CH2:1][N:2]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: c1cc(CN2CCOCC2)ccn1
Reactant: N#Cc1ccnc(CO)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: OCc1cc(CN2CCOCC2)ccn1
Yield: 21 %

Procedure:
In a manner similar to the procedure described for the preparation of 4-cyano-2-hydroxymethylpyridine, 4-(4-morpholinyl)methylpyridine (9.15 g, 51.40 mmol), ammonium persulfate (23.44 g, 102.81 mmol, 2.0 equiv.), methanol (92 ml), water (46 ml) and concentrated H2SO4 (11.59 g, 118.2 mmol, 2.3 equiv.) provided 2.29 g (21%) of 2-hydroxymethyl-4-(4-morpholinyl)methylpyridine.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[C:7]3[N:39]=[C:38]4[N:40]=[C:31]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=54)[N:30]=[C:28]4[NH:29][C:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=54)=[N:20][C:18]4=[N:19][C:11]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=54)=[N:10][C:9]=2[NH:8]3)[CH:6]=1.[Cl:41][S:42]([OH:45])(=O)=[O:43].S(Cl)([Cl:48])=O>O>[CH:2]1[CH:1]=[CH:6][C:5]2[C:4](=[C:9]3[N:10]=[C:11]4[N:19]=[C:18]([C:17]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=54)[N:20]=[C:21]4[NH:29][C:28]([C:27]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=54)=[N:30][C:31]4=[N:40][C:38]([C:37]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=54)=[N:39][C:7]=2[NH:8]3)[CH:3]=1.[S:42]([Cl:41])([Cl:48])(=[O:45])=[O:43]
Reactant: O=S(=O)(O)Cl
Reactant: O=S(Cl)Cl
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: O
Product: O=S(=O)(Cl)Cl
Temperature: 77.5 °C
Reaction time: 1 h

Procedure:
An unsubstituted metallic phthalocyanine compound is added by small portions in three times to ten times amount (by weight) of chlorosulfonic acid while maintaining at 18° C. or less. After stirring at that temperature for 1 hour, the temperature is increased at a rate of 0.5 to 1° C. per minute, and the mixture is reacted at a temperature of 130 to 135° C. for from 4 to 6 hours. Thereafter, the mixture was cooled to 70 to 85° C., thionyl chloride in an amount of twice to six times the amount of the unsubstituted metallic phthalocyanine is added dropwise while maintaining at from 70 to 80° C. over 10 to 15 hours. After stirring for several hours at that temperature, the mixture was cooled to 15 to 20° C. and continuously stirred for from 10 to 15 hours. The reaction mixture is discharged by small portions into iced water in an amount of 50 times to 200 times the amount of the metallic phthalocyanine. The resulting deposit is filtrated and washed with iced water until becoming neutral, followed by drying, to obtain a metallic phthalocyanine sulfonylchloride.
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]=[C:13]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=3[F:23])[S:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.[Na]>CO.C(Cl)Cl>[CH2:1]([C:8]1[CH:25]=[CH:24][C:11]2[N:12]=[C:13]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)=[CH:17][C:16]=3[F:23])[S:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2nc3ccc(Cc4ccccc4)cc3s2)c(F)c1
Reactant: O=C(O)C1CNC1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3nc4ccc(Cc5ccccc5)cc4s3)c(F)c2)C1
Reaction time: 1 h

Procedure:
At 24° C., a mixture of 4-(6-benzylbenzo[d]thiazol-2-yl)-3-fluorobenzaldehyde (190 mg, 547 μmol), azetidine-3-carboxylic acid (166 mg, 1641 μmol), acetic acid (0.095 mL, 1641 μmol) in MeOH (2 mL) and DCM (2 mL) was stirred for 1 h. The light yellow solution was treated with sodium borocyanohydride (34 mg, 547 μmol). The mixture was stirred for 12 h. The solids were filtered off and washed 3× with DCM, suspended in 4 mL of an aqueous buffered solution (phosphate buffer pH 6) and sonicated for 10 min. The mixture was filtered and the solids washed with water and dried in vacuo to yield 1-((4-(6-Benzylbenzo[d]thiazol-2-yl)-3-fluorophenyl)methyl)azetidine-3-carboxylic acid as a white solid [hS1P1 EC50=149 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (t, J=8.4 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.44 (d, J=6.6 Hz, 1H), 7.34-7.29 (m, 6H), 7.21-7.20 (m, 1H), 4.11 (s, 2H), 3.83-3.82 (br. m, 1H), 3.63 (s, 2H), 3.41 (t, J=6.8 Hz, 2H), 3.21 (t, J=7.0 Hz, 2H). MS (ESI) m/z: Calculated: 432.5; Observed: 433.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:27])[C:7]([C:22]([O:24]CC)=[O:23])=[CH:8][N:9]2[C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=2[F:21])=[CH:4][C:3]=1[F:28].Cl.[C:30]([OH:33])(=O)[CH3:31].O.[CH2:35](O)C>>[CH:3]([O:33][CH:30]([CH3:31])[CH3:35])([CH3:4])[CH3:2].[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:27])[C:7]([C:22]([OH:24])=[O:23])=[CH:8][N:9]2[C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=2[F:21])=[CH:4][C:3]=1[F:28]
Reactant: CCO
Reactant: CC(=O)O
Reactant: CCOC(=O)c1cn(-c2cc(NC)c(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: O
Product: CC(C)OC(C)C
Product: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F

Procedure:
Ethyl 7-chloro-1-(2,4-difluoro-5-methylaminophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (150 mg) was added to 1 ml of a mixture of 3N hydrochloric acid and acetic acid (1/1, vol/vol), which was stirred and heated at reflux for 2 hours. After 5 ml of distilled water was added, the reaction solution was heated at reflux for a further 10 minutes and then allowed to cool down. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and then with diisopropyl ether to give 70 mg of the title compound.