Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[F:19][C:2]([F:1])([F:18])[C:3]1[N:7]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: COC(=O)c1ccc(-n2nnnc2C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(-n2nnnc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
To a solution of the compound (5.2 g) obtained in step 1 in THF/methanol/water (6.0/18/9.5 mL) was added 4N aqueous lithium hydroxide solution (9.5 mL), and the mixture was stirred at room temperature for 4 hr. The mixture was acidified with 1N hydrochloric acid, concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried, filtered through silica gel (eluted with ethyl acetate). The filtrate was concentrated under reduced pressure, and crystallized from ethyl acetate/hexane to give the title compound (4.3 g, 86%) as a pale-yellow powder.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:29]=[C:22]3[CH:23]([CH3:28])[N:24]([CH3:27])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=1)(=O)C.[OH-].[Li+].C(O)(C)C.C1COCC1>O>[CH3:28][CH:23]1[N:24]([CH3:27])[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:30])[N:14]([CH3:31])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:32]5[CH2:44][CH2:43][N:35]6[C:36]7[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=7[CH:42]=[C:34]6[C:33]5=[O:45])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:29]=[C:22]12
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4C)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: CC1c2cc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nn2CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287j (60 mg, 1.0 eq., 0.098 mmol), lithium hydroxide (12 mg, 5.0 eq., 0.49 mmol), i-propanol/THF (4/4 mL), and water (1 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 287 as a yellow solid (24 mg, 43%). MS-ESI: [M+H]+ 568.9. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.99 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J=5.0 Hz, 1H), 6.91 (s, 1H), 5.74 (s, 1H), 5.04-5.02 (m, 1H), 4.64-4.62 (m, 1H), 4.56-4.54 (m, 1H), 4.39-4.37 (m, 1H), 4.17-3.92 (m, 4H), 3.86-3.84 (m, 1H), 3.72 (s, 3H), 3.45-3.37 (m, 1H), 3.17-3.14 (m, 1H), 2.89-2.81 (m, 1H), 2.64-2.58 (m, 4H), 2.48 (s, 3H), 1.93-1.89 (m, 2H), 1.81-1.80 (m, 2H), 1.46 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:9]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[C:12]([OH:14])[CH:13]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=2[O:24]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:24]1[C:25]2[CH:26]=[CH:27][C:28]([C:10]3[CH:9]=[C:8]([C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[O:7])[CH:13]=[C:12]([OH:14])[CH:11]=3)=[CH:29][C:30]=2[O:31][CH2:23]1
Reactant: O=C(c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1)C1CCCC1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(c1cc(O)cc(-c2ccc3c(c2)OCO3)c1)C1CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 3-cyclopentanecarbonyl-5-hydroxy-phenyl ester (300 mg) in 1,2-dimethoxyethane (4 mL) were added 3,4-methylenedioxyphenylboronic acid (295 mg), 2 M aq. sodium carbonate solution (0.9 mL) and Pd(PPh3)4 (10 mg) and the resulting mixture was stirred at 90° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 100 mg of the title compound (36% yield). HRMS calcd for C19H18O4 [M+H]+ 311.1278, observed 311.1277.
Reaction SMILES: C(O[C:5]([C:7]1[N:8]([N:13]([C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:10]([F:12])[CH:11]=1)=[O:6])C=C.[O-]CC.[Na+].CO>C(O)C.ClCCl>[CH2:24]([O:23][C:21]([C:20]1[C:19](=[O:26])[N:13]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[N:8]2[CH:9]=[C:10]([F:12])[CH:11]=[C:7]2[C:5]=1[OH:6])=[O:22])[CH3:25]
Reactant: C=CCOC(=O)c1cc(F)cn1N(CCC(C)C)C(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2cc(F)cn2n(CCC(C)C)c1=O
Temperature: 40 °C
Yield: 49.1 %

Procedure:
To a solution of 1-[(2-ethoxycarbonyl-acetyl)-(3-methyl-butyl)-amino]-4-fluoro-1H-pyrrole-2-carboxylic acid allyl ester (Example 14h, 0.318 g, 0.898 mmol) in ethanol (10 mL) was added a 21% solution of sodium ethoxide in ethanol (0.728 g, 2.245 mmol) and the mixture was heated at 40° C. for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes, then 10% methanol in dichloromethane) to afford the desired product, 6-fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (0.137 g, 0.441 mmol, 49.1% yield) as a yellow oil. 1HNMR (400 MHz, CDCl3) δ: 0.99 (3H, s), 1.00 (3H, s), 1.44 (3H, t, J=7.0 Hz), 1.58-1.63 (2H, m), 1.67-1.75 (1H, m), 4.18-4.22 (2H, m), 4.44 (2H, quartet, J=7.1 Hz), 6.55 (1H, m), 7.04 (1H, m).
Reaction SMILES: [C:1](=[O:4])(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].[C:9]1(C)[C:10](C)=[CH:11][CH:12]=[CH:13][CH:14]=1>>[NH2:7][C:6]1[NH:8][C:1](=[O:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[N:5]=1
Reactant: N=C(N)N
Reactant: O=C(O)O
Reactant: Cc1ccccc1C
Product: Nc1nc2c(c(=O)[nH]1)CCCC2

Procedure:
A mixture of ethyl-2-cyclohexanone carboxylate (2.0 g) and guanidine carbonate (2.66 g) in xylene (40 ml) was refluxed overnight; after cooling the solid was collected by filtration, washed with water, methanol, and dried over MgSO4. 0.6 g of a white solid having a m.p. >300° C. was recovered. The solid was dissolved in Con. HCl, and excess HCl was removed in vacuo to dryness. The gummy residue was treated with methanol-ether to afford a colorless plate (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1C=[CH:13][N:12]=[N:11]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][C:27]=1[O:41][CH3:42].[NH:43]1[CH:47]=[N:46][N:45]=[N:44]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[N:11]=[N:12][CH:13]=[N:36]1.[CH3:42][O:41][C:27]1[CH:28]=[C:29]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[CH:30]=[CH:31][C:26]=1[CH2:25][N:43]1[CH:47]=[N:46][N:45]=[N:44]1
Reactant: c1nnn[nH]1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1cnnn1
Product: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ncnn1

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and 1H-tetrazole (70 mg, 1.0 mmol) afforded 2-[3-methoxy-4-(2H-tetrazol-2-ylmethyl)phenyl]-1,3-benzoxazole and 2-[3-methoxy-4-(1H-tetrazol-1-ylmethyl)phenyl]-1,3-benzoxazole as colorless solids. 2-[3-methoxy-4-(2H-tetrazol-2-ylmethyl)phenyl]-1,3-benzoxazole: 1H NMR (CDCl3, 300 MHz) δ 8.52 (s, 1H), 7.72–7.79 (m, 3H), 7.52–7.55 (m, 1H), 7.31–7.34 (m, 2H), 7.21 (d, 1H), 5.86 (s, 2H), 3.93 (s, 3H). MS (ESI) 308 (M+H). 2-[3-methoxy-4-(1H-tetrazol-1-ylmethyl)phenyl]-1,3-benzoxazole: 1H NMR (CDCl3, 300 MHz) δ 8.66 (s, 1H), 7.85 (d, 1H), 7.74–7.83 (m, 2), 7.55–7.59 (m, 1H), 7.41 (d, 1H), 7.34–7.40 (m, 2H), 5.61 (s, 2H), 3.98 (s, 3H). MS (ESI) 308 (M+H)+.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC(OC)=O.C(N(CC)CC)C.[NH2:26][C:27]([CH3:34])([CH:31]([CH3:33])[CH3:32])[C:28]([NH2:30])=[O:29]>O1CCCC1.O>[C:28]([C:27]([NH:26][C:1](=[O:13])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)([CH3:34])[CH:31]([CH3:33])[CH3:32])(=[O:29])[NH2:30]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of quinaldic acid (20 g, 0.116 mol) in tetrahydrofuran (500 ml) cooled to -9° C. is added methyl chloroformate (8.92 ml, 0.116 mol) followed by triethylamine (18.4 ml, 0.139 mol). After 20 minutes 2-amino-2,3-dimethylbutyramide (15.1 g, 0.116 mol) is added and the mixture stirred overnight at room temperature. Water is added and the solution is reduced to 200 ml of a rotorvap. A white solid separates and is filtered off, water washed and dried. Recrystallization from absolute ethanol gives the product mp 179°-180° C., 26.86 g (87%). Anal. calcd. for C16H19N3O2 : C, 67.34; H, 6.73; N, 14.72. Found: C, 67.14; H, 6.17; N, 14.72.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][CH3:25])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[C:7]2[O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21].[N:26]1([C:32]2[CH:37]=[CH:36][C:35]([NH-:38])=[CH:34][CH:33]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH3:39][N:40]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[N:26]1([C:32]2[CH:33]=[CH:34][C:35]([NH:38][C:12]([C:9]3[CH:8]=[C:7]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:6]4[C:11](=[C:2]([N:43]5[CH2:44][CH2:45][CH2:46][N:40]([CH3:39])[CH2:41][CH2:42]5)[CH:3]=[C:4]([O:24][CH3:25])[CH:5]=4)[N:10]=3)=[O:14])=[CH:36][CH:37]=2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: CN1CCCNCC1
Reactant: [NH-]c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(Br)c2nc(C(=O)O)cc(OCOCC[Si](C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COc1cc(N2CCCN(C)CC2)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(OCOCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a yellow-green suspension of 8-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid (Reference Example 27c) (4-morpholin-4-yl-phenyl)-amide (1.155 g, 1.96 mmol), N-methyl homopiperazine (0.39 mL, 3.14 mmol), and 4 Å sieves in 30 mL anhydrous toluene was added Pd2 (dba)2 (90.0 mg, 0.098 mmol) and BINAP (0.358 g, 0.58 mmol). The resulting reddish brown mixture became lighter in color upon treatment with cesium carbonate (2.544 g, 7.81 mmol). The reaction mixture was heated at reflux under nitrogen for 17 hours. The clear brown solution was cooled to room temperature, concentrated, and then purified by flash chromatography on silica gel using a slow gradient of 95:5 to 50:50 methylene chloride:methanol to afford the desired product (0.989 g, 81%). 1H NMR (300 MHz, DMSO, d6) δ 9.88 (s, 1 H, NH), 7.73 (s, 1 H, ArH3), 7.68 (d, 2 H, Jo=8.9 Hz, ArH2′& H6′), 7.00 (d, 2 H, Jo=8.9 Hz, ArH3′& H5′), 6.94 (d, 1 H, Jm=2.7 Hz, ArH5), 6.66 (d, 1 H, Jm=2.7 Hz, ArH7), 5.62 (s, 2 H, OCH2O), 3.87 (s, 3 H, OCH3), 3.80(t, 2 H, J=8.0 Hz, OCH2CH2Si), 3.73 (t, 4 H, J=4.7 Hz, OCH2CH2N), 3.63 (t, 2 H, J=5.9 Hz, ArNCH2CH2CH2NCH3), 3.33 (bs, 2 H, ArNCH2CH2NCH3), 3.09 (t, 4 H, J=4.7 Hz, OCH2CH2N), 2.97 (bs, 2 H, ArNCH2CH2NCH3), 2.69 (bs, 2 H, ArNCH2CH2CH2NCH3), 2.35 (s, 3 H, NCH3), 2.09 (bs, 2 H ArNCH2CH2CH2NCH3), 0.94 (t, 2 H, J=8.0 Hz, OCH2CH2Si), −0.03 (s, 9 H, Si(CH3)3; Mass Spec.: calc. for [C33H47N5O5Si+H]+ Theor. m/z=622; Obs.=622.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][C:9](=O)[CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3][CH2:2]1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C1C=CC=CC=1>[C:12](/[C:14](=[C:9]1\[CH2:8][CH2:7][O:6][C:5]2([CH2:10]\1)[CH2:4][CH2:3][CH2:2][CH2:1]2)/[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: COC(=O)CC#N
Reactant: O=C1CCOC2(CCCC2)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C(C#N)=C1/CCOC2(CCCC2)C1

Procedure:
A 100 ml round-bottom flask equipped with a Dean-Stark distillation setup and condenser was charged with 6-oxaspiro[4.5]decan-9-one (6 g, 39 mmol, which was prepared according to Hanschke, E. Chem. Ber. 1955, 88, 1053), methyl cyanoacetate (4.1 ml, 46.7 mmol), ammonium acetate (780 mg, 10.1 mmol), acetic acid (0.44 ml, 7.8 mmol) and benzene (40 ml). The mixture was refluxed until no more water collected in the Dean-Stark (2 hours), cooled, benzene (30 ml) added and the organic washed with water (50 ml). The aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic phase was washed with sat. NaHCO3 (100 ml), brine (100 ml) dried (MgSO4), filtered and concentrated. Purified by normal phase SiO2 chromatography (7% to 60% EtOAc/hexanes) to give methyl 2-cyano-2-[(9Z)-6-oxaspiro[4.5]decan-9-ylidene]acetate as a colorless oil (8.93 g, 97.5%, m/z 235.1 [M+H]+ observed).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[SiH](Cl)Cl>C1(C)C(C)=CC=CC=1>[CH3:1][S:2]([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CS(=O)(=O)Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 150 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
3.93 gram (7.17 mmol) of (−)-2-methylsulfonylamino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-3a-1)) was dissolved in 179 ml of xylene in an autoclave, followed by the addition of 20.0 ml (143.4 mmol) of triethylamine at 0° C. over 15 minutes and 3.62 ml (35.8 mmol) of trichlorosilane over 30 minutes. The mixture was stirred at 150° C. for 18 hours in a tightly sealed condition. The reaction mixture was then extracted with 300 ml of ether. The extract was washed with 100 ml of saturated aqueous solution of ammonium chloride and 100 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:6 mixture of ethyl acetate and hexane) to obtain 3.35 gram of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[NH2:13].CCN(C(C)C)C(C)C.[CH2:28]([CH2:30][NH2:31])[OH:29]>CCCCO>[Cl:9][C:10]1[CH:11]=[C:12]([NH:13][C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:31][CH2:30][CH2:28][OH:29])[CH:7]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NCCO
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ccc(N)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(Nc2cc(NCCO)ncn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
100 mg of 4,6-dichloropyrimidine, 106 mg of 3-chloro-4-methoxyaniline and 103 mg of DIPEA were dissolved in 1 mL n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was kept overnight in a heating block at 120° C. The reaction was monitored by TLC and was completed after 12 hours. The mixture obtained was cooled to r.t., 61 mg of ethanolamine and 139 mg of were added and the mixture obtained was heated under microwave irradiation for an hour at 200° C. The reaction was finished and crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 20:1. 2-(6-(3-Chloro-4-methoxyphenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH3:25][P:26]([CH2:29]Cl)([CH3:28])=[O:27].O>CN(C)C=O>[CH3:25][P:26]([CH2:29][N:14]1[CH2:15][CH2:16][CH:11]([O:10][C:9]2[C:17]([F:24])=[C:18]([F:23])[C:19]([F:22])=[C:20]([F:21])[C:8]=2[F:7])[CH2:12][CH2:13]1)([CH3:28])=[O:27]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CP(C)(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CP(C)(=O)CN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 80 °C
Reaction time: 30 h
Yield: 22.2 %

Procedure:
To a stirring mixture of 9.0 g of potassium carbonate in 100 ml of dimethylformamide was added 8.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 9.5 g of dimethylphosphinylmethyl chloride. After stirring at 80° C. for 30 hours, the reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 5% methanol/dichloromethane). The desired fractions were evaporated to yield a solid which was sublimed to afford 2.37 g (22.1%) of 1-[(dimethylphosphinyl)methyl]-4-(2,3,4,5,6-pentafluorophenoxy) piperidine, m.p. 120°-123° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:10]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:9]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(NS(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[5-(benzenesulfonamido)-6-(2-phenylethynyl)pyridin-2-yl]-carbamate C5a (37 mg, 0.08 mmol) and DCM:TFA (9:1, 4 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The crude D5a (27 mg) is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13].C(#N)C.P(Cl)(Cl)([Cl:19])=O>C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:19])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[F:13]
Reactant: Oc1ccnc2cc(Br)c(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Fc1cc2c(Cl)ccnc2cc1Br
Temperature: 90 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
A vial was charged with 7-bromo-6-fluoroquinolin-4-ol (0.460 g, 1.900 mmol) and acetonitrile (9.50 ml). Phosphoryl trichloride (0.354 ml, 3.80 mmol) was then added, and the reaction was stirred for 2 h at 90° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous was extracted once more with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The material was then purified via silica gel chromatography eluting with 0-75% ethyl acetate in heptanes to yield 7-bromo-4-chloro-6-fluoroquinoline (0.141 g, 0.541 mmol, 28.5% yield) as a white solid. m/z (ESI) 260.1 (M+H)+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4](CC)=[CH:5][C:6]2[N:12]3[C:13]([NH:19][CH3:20])=[NH+:14][N:15]([CH2:16]CC)[CH:11]3[CH:10](C)[N:9]=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([N+]([O-])=[O:29])=[CH:24][CH:23]=3)[C:7]=2[CH:31]=1.C(=O)(O)[O-].[Na+]>>[OH-:29].[NH:19]([C:13]1[N:12]2[C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:31][C:7]=3[C:8]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:9][CH2:10][CH:11]2[N:15]([CH3:16])[NH+:14]=1)[C:20]1[CH:5]=[CH:4][CH:3]=[CH:31][CH:7]=1
Reactant: CCCN1[NH+]=C(NC)N2c3cc(CC)c(Cl)cc3C(c3ccc([N+](=O)[O-])cc3)=NC(C)C12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Product: CN1[NH+]=C(Nc2ccccc2)N2c3ccc(Cl)cc3C(c3ccccc3)=NCC12
Product: [OH-]

Procedure:
The residue containing 1-anilino-8-chloro-3-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinium chloride (VIII) (obtained in A, above) is mixed with cold, dilute aqueous sodium bicarbonate solution and extracted with chloroform. The extract is washed with brine, dried with sodium sulfate and concentrated. The residue is crystallized to give 1-anilino-8-chloro-3-methyl-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepinium hydroxide inner salt (XI).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (7.77 g, 25.3 mmol) in methanol (50 mL) was treated slowly with concentrated sulfuric acid (0.01 mL). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (75 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (1×50 mL), and a saturated aqueous sodium chloride solution (4×50 mL). The combined organic layers were dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid methyl ester (8.48 g, 87.5%) as yellow oil: EI-HRMS m/e calcd for C16H18F4O2 (M+) 318.1243, found 318.1240.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[C:8]#[N:9].[OH2:18].N>O>[NH2:6][CH:7]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[C:8]([NH2:9])=[O:18]
Reactant: O
Reactant: N#CC(N)c1ccc(Cl)cc1Cl
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1ccc(Cl)cc1Cl
Reaction time: 3 h
Yield: 57 %

Procedure:
Then, 11.2 g of concentrated sulfuric acid was added to 0.54 g of water, to which 10.1 g of 2-amino-2-(2,4-dichlorophenyl)acetonitrile was added under ice cooling, and the mixture was heated at 50° to 60° C. under stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into 30 ml of concentrated ammonia water cooled with ice in such a manner that the temperature of the solution became not higher than 20° C. The precipitated crystals were collected by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was combined with the previously collected crystals, followed by recrystallization, which afforded 6.14 g (yield, 57%) of 2-amino-2-(2,4-dichlorophenyl)acetamide, m.p. 113.8° C.