Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][NH:29][CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH2:68]([N:70]([CH2:76][CH3:77])[CH2:71][CH2:72][C:73](O)=[O:74])[CH3:69]>CN(C=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[C:23]5[CH2:31][CH2:30][N:29]([C:73](=[O:74])[CH2:72][CH2:71][N:70]([CH2:76][CH3:77])[CH2:68][CH3:69])[CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)CCC(=O)O
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CCNC4)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCC(=O)N1CCc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide, Example 31-C, (120 mg, 0.26 mmol), HATU (198 mg, 0.52 mmol), DIEA (0.2 mL, 1.30 mmol) and DMF (5 mL) is added 3-diethylamino-propionic acid hydrochloride (47 mg, 0.26 mmol). After stirring at rt for 2 h the contents of the flask are partitioned between DCM and 10% aqueous LiCl. Organic layer is removed, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is then separated via semi-prep HPLC (C18; 10-100% I/H2O with 0.1% NH4OH) to give the title compound. MS (ESI) m/z 581.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.40-8.48 (m, 1 H), 8.33 (d, J=8.8 Hz, 1 H), 8.06 (s, 1 H), 7.94 (d, J=3.5 Hz, 1 H), 7.89 (d, J=8.6 Hz, 1 H), 7.57 (t, J=8.1 Hz, 1 H), 7.36-7.47 (m, 2 H), 7.10 (dd, J=9.0, 2.1 Hz, 1 H), 6.74 (d, J=3.8 Hz, 1 H), 4.71-4.79 (m, 2 H), 3.85-4.05 (m, 2 H), 3.20 (d, J=5.8 Hz, 2 H), 2.84-3.08 (m, 8 H), 1.23 (q, J=7.1 Hz, 6 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[CH:23][C:22]=1[CH3:28].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([CH3:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: C1COCCN1
Reactant: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCCCCCCN1CCOCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 6) and morpholine following the procedure outlined in Example 15 (modifications: 25° C., 16 h; then 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 8.40 (s, 1H), 8.39 (s, 2H), 7.88 (d, 1H), 7.01 (d, 1H), 4.51 (s, 1H), 3.96 (t, 2H), 3.89 (s, 3H), 3.53 (m, 4H), 2.29 (br, 4H), 2.22 (t, 2H), 2.13 (s, 6H), 1.74 (m, 2H), 1.39 (m, 4H), 1.31 (m, 2H); MS (ESI): 481.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32]Br)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>CCO>[C:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11](=[O:20])[O:12]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1ccc(CCCBr)cc1
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Solvent: CCO
Product: CC(=O)c1ccc(CCCOc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)cc1
Yield: 76.6 %

Procedure:
Alkylation of 4-benzyloxy-7-hydroxycoumarin (2.68; 0.01 mole) with 1-(4-acetylphenyl)-3-bromopropane (2.41 g; 0.01 mole) as described in Example 45 gave 3.28 g (77%) of title compound of m.p. (EtOH) 117° νmax (mull) 1725, 1682, 1620 cm-1 ; τ(DMSO) 7.92 (2H, m); 7.48 (3H, s); 7.18 (2H, m); ; 5.94 (2H, t, J 6.4 Hz); 6.69 (2H, s); 6.16 (1H, s); 3.17-2.00 (12H, m). (Found; C, 75.14; H, 5.52; C21H24O5 requires; C, 75.68; H, 5.65%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:26])([CH3:25])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:24])[CH3:23])=[CH:14][C:13]=2[CH3:27])=[CH:7][CH:6]=1)[CH3:2].[CH:29](=O)[CH2:30][CH3:31].C([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:21]=[C:20]3[C:15]([C:16]([CH3:25])([CH3:26])[CH2:17][CH2:18][N:19]3[CH:22]([CH3:23])[CH3:24])=[CH:14][C:13]=2[CH3:27])[CH2:29][CH2:30][CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCC=O
Reactant: CCOC(=O)c1ccc(Nc2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCN(c1ccc(C(=O)OCC)cc1)c1cc2c(cc1C)C(C)(C)CCN2C(C)C
Yield: 17.9 %

Procedure:
A solution of 4-(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-ylamino)-benzoic acid ethyl ester (Compound 46, 60.3 mg, 0.1585 mmol), propionaldehyde (36.4 mg, 0.792 mmol), sodium cyanoborohydride (49.77 mg, 0.792 mmol), acetic acid (0.125 mL), and acetonitrile (1 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.44) to give the title compound (12.0 mg, 18%) as a solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH3:24])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC(=O)CCl
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1
Product: CC(CCl)=NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-fluoro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 7-fluoro-2-[(2-chloro-1-methylethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[C:24](O)(=[O:28])[CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CCCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and butyric acid to yield (3aR,4S,7aR)-4-butyryloxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=1.40 min; UPLC Method I
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([C:24](=[O:29])C(F)(F)F)=[CH:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:32]>CN(C)C=O.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([C:24]([OH:32])=[O:29])=[CH:15]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(C(=O)O)c2ccc(Cl)cc21
Reaction time: 0.75 h
Yield: 92.4 %

Procedure:
To a solution of 1.7 g (4.0 mmol) (S)-2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester and 1.0 g (22 mmol) sodium hydride (50% in oil) in 40 ml dry N,N-dimethylformamide were added dropwise 0.36 ml (20 mmol) water under water-bath cooling. After stirring for 45 min the reaction mixture was diluted with 80 ml tert-butyl methyl ether. The organic layer was extracted with aqueous 1 M sodium hydroxide solution (2×100 ml). The combined aqueous layers were acidified to pH 2 with ice-cold aqueous hydrochloric acid solution and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate layers were dried over sodium sulfate and concentrated to dryness to give the title compound (1.4 g, 96%) as a light yellow solid.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O/[CH:7]=[CH:8]/[C:9](=O)[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])C>CO>[CH3:1][N:2]1[CH:7]=[CH:8][C:9]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[N:3]1
Reactant: CCO/C=C/C(=O)C(F)(F)C(F)(F)F
Reactant: CNN
Solvent: CO
Product: Cn1ccc(C(F)(F)C(F)(F)F)n1

Procedure:
7.18 g (156 mmol) of methylhydrazine are added dropwise to a solution of 30.9 g (142 mmol) of (1E)-1-ethoxy-4,4,5,5,5-pentafluoropent-1-en-3-one (preparation: Synthesis 2000, 5, 738-742) in 56 ml of methanol, and the reaction mixture is heated under reflux for 18 hours. The majority of the methanol is distilled off at atmospheric pressure and the residue is poured on to ice. The aqueous phase is extracted three times with dichloromethane and the organic phase is then washed three times with saturated sodium chloride solution. After drying over sodium sulphate, the solvent is distilled off at reduced pressure on a rotary evaporator. This gives 15.8 g of 1-methyl-3-pentafluoroethyl-1H-pyrazole (52%) as an oil.
Reaction SMILES: Cl[C:2]([C:4]1[CH:19]=[CH:18][C:7]2[C:8](=[O:17])[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=1)=[O:3].[Na].[OH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>O1CCCC1>[O:17]=[C:8]1[C:7]2[CH:18]=[CH:19][C:4]([C:2]([O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:3])=[CH:5][C:6]=2[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[NH:9]1
Reactant: O=C(O)CCO
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1NC2=O
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCOC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm. of 3-chlorocarbonyl-10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepine in 20 cc. of tetrahydrofuran and add 1.0 gm. of the sodium salt of β-hydroxypropionic acid. Stir the mixture at room temperature for 18 hours. Filter and evaporate the filtrate to dryness. Recrystallize the solid residue from ethanol to obtain the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NCCC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NCCC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(3,3-dimethyl-butyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:27]([CH:20]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:28])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C1CCCCCC1
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)C1CCCCCC1
Yield: 29.7 %

Procedure:
A solution of amine 8 (0.200 g, 0.78 mmol) in dry Pyridine (5 ml) and cycloheptane carbonyl chloride (0.200 ml, 1.24 mmol) was heated at 80° C. for 2 h. The reaction was quenched by addition of water and the yellow product was filtered, air dried and passed through a SiO2 gel column. Eluting with hexane: EtOAc (6:4) yielded the desired product 18 (0.088 g, 30%); 1H NMR (DMSO-d6, 500 MHz): δ10.38 (1H, brs, NH), 8.76 (1H, brs, NH), 8.44-8.39 (4H, m), 8.33 (1H, brs), 2.92 (1H, m), 1.86-145 (12H, m), EIMS m/z: 380 (M+1), 739.1 (M+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:33]=1[NH:32][C:31]([C:34](O)=[O:35])=[CH:30]2>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:31]3[NH:32][C:33]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][C:25]=4[F:24])=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: O=C(O)c1cc2cccc(F)c2[nH]1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cc4cccc(F)c4[nH]3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 7-fluoro-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.92 min; [M+H]+=493.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].[CH2:26]([O:28][C:29]([C:31]1[N:32]=[C:33]([CH2:36]Br)[O:34][CH:35]=1)=[O:30])[CH3:27]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:36][C:33]4[O:34][CH:35]=[C:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[N:32]=4)[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: CCOC(=O)c1coc(CBr)n1
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCOC(=O)c1coc(Cn2cc(C3c4ccc(CC)cc4C=Cc4oc(C)nc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product of example 3 step (vii) (2.2 g) and 2-bromomethyl-4-oxazolecarboxylic acid ethyl ester (0.52 g) using the method of example 1 step (viii). Purification was by chromatography eluting with ethyl acetate.
Reaction SMILES: OC1[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[C:27]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)(N1C=CN=C1)=O>C1COCC1>[N:34]1([CH:27]2[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]3[CH:7]=[C:6]([C:14]#[C:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=4)[CH:5]=[CH:4][C:3]2=3)[CH:38]=[CH:37][N:36]=[CH:35]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3n2ccnc2)cc1
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A solution of methyl [4-(5-hydroxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl)-phenyl]-acetate (Compound 135, 140.0 mg, 0.40 mmol) and carbonyldiimidazole (136.0 mg, 0.84 mmol) in 5 mL THF was heated to 65° C. for 48 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in Et2O and washed with 5% aqueous NaOH, H2O, and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (5% MeOH—CH2Cl2) afforded 50.0 mg (31%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])=[CH:5][CH:4]=1)[CH3:2].CO.[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)OC)cc3)nn2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1ccc(-c2c(O)c(C(C)=NNC(=O)c3ccc(C(=O)O)cc3)nn2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To methyl 4-[(2-{1-[5-(4-ethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.172 mmol, 72.4 mg), methanol (4 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.861 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.861 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (29.1 mg, yield 42%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 100 %

Procedure:
A mixture of 2.00 g (10.0 mmol) of 1-t-butoxycarbonyl-4-piperidone, 35 ml of benzene and 1.05 g (12.1 mmol) of morpholine was refluxed and the formed water was removed by using a Dehn-Stark dehydrating tube. After completion of distillation of water, the reaction mixture was concentrated under reduced pressure to obtain 2.69 g (10.0 mmol) of 1-t-butoxycarbonyl-4-morpholino-1,2,5,6-tetrahydropyridine as yellowish solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4](C(OCC2C=CC=CC=2)=O)[CH2:3]1.[C:16]([O:20][C:21]1[N:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>C1COCC1>[NH:4]1[CH2:3][CH:2]([O:1][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:26][CH:25]=2)[CH2:5]1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Reactant: CC(C)(C)Oc1ccc(O)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(OC2CNC2)cn1
Temperature: 55 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
Benzyl 3-hydroxyazetidine-1-carboxylate (2.3 g) and 6-tert-butoxypyridin-3-ol (1.5 g) were mixed with THF (25 ml), and triphenylphosphine (4 g) was added thereto. A 1.9 M DIAD/toluene solution (8 ml) was added dropwise thereto, followed by stirring at 55° C. overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was mixed with ethanol (25 ml), and 10% palladium carbon (800 mg) were added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-(azetidin-3-yloxy)-2-tert-butoxypyridine (595 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:13][C:14]1[C:15]([OH:54])=[C:16]([S:21]([N:24]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=2)[CH2:25][C:26]2[CH:31]=[C:30]([CH2:32][NH:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:29]=[C:28]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:27]=2)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1.CCN(CC)CC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:13][C:14]1[C:15]([OH:54])=[C:16]([S:21]([N:24]([CH2:25][C:26]2[CH:27]=[C:28]([O:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[CH:29]=[C:30]([CH2:32][N:33]([CH2:34][CH:35]([CH3:37])[CH3:36])[S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])[CH:31]=2)[CH2:46][C:47]2[CH:48]=[CH:49][C:50]([F:53])=[CH:51][CH:52]=2)(=[O:23])=[O:22])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)CNCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CN(Cc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To a solution of 3,5-dichlorobenzenesulfonyl chloride (27.0 mg, 0.11 mmol) in CH2Cl2 (3 mL) was added 3,5-dichloro-N-(4-fluorobenzyl)-N-(3-(4-fluorophenoxy)-5-((isobutylamino)methyl)benzyl)-2-hydroxybenzenesulfonamide (70 mg, 0.11 mmol, 80% purity), followed by the addition of Et3N (0.09 mL, 0.66 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with CH2Cl2 and saturated NaHCO3 solution. The organic layer was concentrated. To the residue was added 1 N NaOH/MeOH/THF. The resulting mixture was left for 2 h. The mixture was concentrated and the residue was diluted with CH2Cl2 and water. The organic layer was concentrated. The residue was dissolved in MODEL and purified by preparative HPLC. Fractions containing the desired product were combined, concentrated, and lyophilized to give a white solid (35 mg, 38%). 1H NMR (CD3OD): δ 7.67-7.63 (m, 4H), 7.57 (d, J=2.8 Hz, 1H), 7.14-7.04 (m, 4H), 6.91 (t, J=8.8 Hz, 2H), 6.87-6.83 (m, 2H), 6.70 (s, 1H), 6.63 (s, 1H), 6.56 (s, 1H), 4.40 (s, 2H), 4.32 (s, 2H), 4.21 (s, 2H), 2.91 (d, J=7.6 Hz, 2H), 1.65 (m, 1H), 0.74 (d, J=6.4 Hz, 6H); MS (ESI): (M−H)−=843.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nc(-c2cccc(F)c2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3cccc(F)c3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(3-fluorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 44 (11% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.90 and 3.13 (2t, 2H), 3.56 and 4.17 (2t, 2H), 3.83-3.91 (4s, 6H), 4.47 and 5.07 (2s, 2H), 6.52 and 6.91 (2d, 1H), 6.72 and 7.02 (2d, 1H), 7.22-7.23 (m, 1H), 7.49-7.65 (m, 2H), 7.94-8.18 (m, 3H), 8.33-8.47 (m, 2H); MS (ESI) m/z 444 ([M+H]+).