Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=[O:19])[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].O>CN(C)C=O.C(OCC)(=O)C>[CH3:27][O:26][C:24]([CH2:23][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]([C:14]=23)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:25]
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(-c2ccccc2)c2c3c(cccc31)C(=O)CC2
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A solution of the compound (1.37 g) obtained in Example 41 in anhydrous dimethylformamide (DMF; 60 ml) was added to a suspension of sodium hydride (60% dispersion in oil; 0.30 g) in DMF(10 ml) at room temperature. After stirring for 15 minutes, a solution of methyl bromoacetate (0.72 ml) in DMF (10 ml) was added to the reaction mixture. The reaction mixture was stirred for 10 minutes at room temperature, followed by addition of water and extraction with three portions of ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ethyl acetate to yield 1.58 g (90%) of the titled compound as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13]CC)=[O:12])=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[CH3:18].[OH-].[Na+].Cl>CO.C1COCC1>[OH:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=[O:12])=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[C:3]=1[CH3:18]
Reactant: CCOC(=O)c1oc2c(O)c(C)c(C)cc2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(C)c(C(=O)O)oc2c(O)c1C
Temperature: 0 °C

Procedure:
Ethyl 7-hydroxy-3,5,6-trimethylbenzofuran-2-carboxylate (90 g, 0.37 mole) (from Example 2, Step 3) was dissolved in 1:1 MeOH/THF (600 mL) and cooled to 0° C. Dropwise addition of 2N NaOH (750 mL) followed by warming to room temperature for a 2 hr period effected saponification of the ester. The reaction was acidified with conc. HCl (150 mL) and the product extracted into EtOAc, dried (Na2SO4) and the solvent evaporated to give the carboxylic acid used directly in the next step.
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=1>ClCCl>[C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccccc2N)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccccc2NC(=S)NC(=O)c2ccccc2)c1

Procedure:
A mixture of benzoylisothiocyanate (4 g), 2-amino-3'-methanesulphonylbiphenyl (6.1 g) and dichloromethane (30 ml) at ambient temperature for two hours gave N-benzoyl-N'-(3'-methanesulphonyl-2-biphenylyl)thiourea (m.p. 179°-180° C.).
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:22]([O:29][CH2:30][C:31](=[O:41])[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[F:42][C:43]([Si](C)(C)C)([F:45])[F:44].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C1(C)C=CC=CC=1>[F:42][C:43]([F:45])([F:44])[C:31]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:41])[CH2:30][O:29][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC(COCc1ccccc1)(COCc1ccccc1)C(F)(F)F
Reaction time: 0.05 h
Yield: 101.8 %

Procedure:
Tetrabutylammonium fluoride trihydrate (TBAF 3H2O) (2.9 g, 0.5 equivalent) was dissolved in THF (5 ml). This was added cautiously to a stirred and cooled (+15° C.) solution of 1,3-dibenzyloxy-2-propanone in toluene (24.65 g, equivalent to 5 g of the ketone) and (trifluoromethyl)trimethylsilane (7.5 ml). There was an exotherm and a lot of gas evolution on addition of the first 1 ml of TBAF solution. The temperature rose from 18 to 40° C. The TBAF addition was carried out over 3 minutes and then the mixture was stirred at 15-30° C. for a further 2 minutes and then cooled to +10° C. while carrying out an HPLC analysis. The reaction mixture was sequentially washed with 1M aqueous hydrochloric acid (50 ml), 1% aqueous sodium chloride solution (2×25 ml) and a mixture of 1% sodium chloride (25 ml) and saturated sodium bicarbonate (5 ml) solution. The separated organic extract was concentrated in vacuo to give 6.41 g of the desired product as dark brown oil in 101.8% yield. The NMR spectrum showed the presence of residual toluene (8.8%) and starting material (ca 3%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=2[CH2:9][CH2:8]1.[CH2:17](Br)[CH:18]=[CH2:19]>CN(C)C=O.O>[CH2:19]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][CH2:8][CH2:7]2)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1cccc2c1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cccc2c1CCC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of potassium carbonate (23.49 g, 0.170 mol) in N,N-dimethylformamide (350 mL) was added indan-4-ol (7.60 g, 0.057 mol) followed by allyl bromide (8.22 g, 0.068 mol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (1000 mL) to dissolve any solids and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (4×500 mL), aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give 4-(allyloxy)indane. The allyl ether was dissolved in mesitylene (40 mL) and heated at reflux for 8 h. Removal of the solvent in vacuo provided 5-allylindan-4-ol, which was re-dissolved in N,N-dimethylformamide (250 mL). Potassium carbonate (14.28 g, 0.103 mol), benzyl bromide (6.48 g, 0.038 mol), and tetrabutylammonium iodide (2.54 g, 0.007 mol) were added to the reaction mixture. The reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (1000 mL) to dissolve any solids and extracted with diethyl ether (3×250 mL). The combined organic layers were washed with water (4×500 mL), aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 10.22 g (68%) of 5-allyl-2,3-dihydro-1H-inden-4-yl benzyl ether as a pale yellow oil. Rf=0.45 (silica, ethyl acetate:hexanes 1:19); Anal. calcd. for C19H20O: C, 86.32; H, 7.63. Found: C, 85.90; H, 7.49.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[O:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:14]=3[CH2:13][CH2:12][C:11]=2[CH:24]=1.[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:26]1([CH2:29][N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[O:16][C:15]4[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:4][CH2:3][CH:2]([CH3:25])[CH3:1])[CH2:28][CH2:27]1
Reactant: CC(C)CCNCc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)CCN(Cc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2)CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of amine of example 1 (30 mg, 0.09 mmol) in MeOH-AcOH 5% (0.5 mL) add cyclopropanecarboxaldehyde (0.18 mmol). Stir the mixture at room temperature overnight. Add NaBH3CN and stir the mixture at room temperature for about two hours. Add more aldehyde (1.5 mmol) and stir overnight. Purify by SCX ion-exchange chromatography to obtain the title compound (22 mg). 1H-NMR (CD3OD, 300 MHz): 7.72-7.69 (m, 2H), 7.21-7.09 (m, 4H), 3.64 (s, 2H), 3.14 (bs, 4H), 2.61-2.56 (m, 2H), 2.37 (d, 2H, J=6.5 Hz), 1.60-1.37 (m, 4H), 0.87 (d, 6H, J=6.7 Hz), 0.55-0.49 (m, 2H), 0.13-0.08 (m, 2H). Electrospray MS M+1 ion=393.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C(O[C:14](=[O:25])[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=1)C.[CH3:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=1[OH:35])=[O:28]>O1CCCC1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([C:14](=[O:25])[CH2:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=2[OH:35])=[O:28])[CH:16]=[C:17]([O:23][CH3:24])[CH:18]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)c1cc(OC)cc(OC)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)CC(=O)c2ccc(O)cc2O)c1

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (144 mL, 172 mmol), 2,4-dihydroxy acetophenone, 14 (6.5 g, 43 mmol) in tetrahydrofuran (150 mL) and ethyl-3,5-dimethoxy benzoate, 6 (9 g, 43 mmol) in tetrahydrofuran (100 mL) were reacted to afford 20, 1-(3,5-dimethoxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (15 g), which was cyclized with Dowex-H+ (5 g) in 2-propanol (200 mL) in a similar way as described for 22 to afford 26. Yield 7.6 g (59%); mp 267-268° C.; MS (FAB) 299 (M++1); IR (KBr) 3405, 1602; 1H NMR (200 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.17 (d, J=2.0 Hz, 2H), 7.03 (d, J=1.9 Hz, 1H), 6.95 (s, 1H), 6.94 (dd, J=7.2 Hz, 2.0 Hz, 1H), 6.71 (s, 1H), 3.85 (s, 6H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:9])[CH3:8].[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(OC(C)=O)C.O>CN(C=O)C.CCCCCC.CCOC(C)=O>[CH3:19][O:20][C:21](=[O:32])[C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]([CH:7]([CH3:9])[CH3:8])=[CH:11]2)(=[O:29])=[O:30])=[CH:26][CH:27]=1
Reactant: CC(C)c1c[nH]c2ccccc12
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)n2cc(C(C)C)c3ccccc32)cc1
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
Add potassium tert butoxide 1.0 M (1.6 mL, 0.0016 mol) dropwise to a stirring solution of 3-isopropyl indole (0.217 g, 00136 mol) in dry DMF (20 mL) under N2 at ambient temperature. Stir the reaction mixture for 30 minutes and add portionwise 4-chlorosulfonyl benzoic acid methyl ester (0.328 g, 0.0014 mol). The light brown reaction mixture decolorizes immediately. Stir the resulting yellow solution overnight. Pour into a EtOAc—H2O mixture (100 to 300 mL). Separate the EtOAc and sequentially extract with H2O (3×250 mL), wash with brine, dry (MgSO4), filter and evaporate giving 0.38 g. Chromatograph on the ISCO using a gradient hexane-EtOAc (0-50%, 30 30 minutes) to give 0.249 g (51%) of the title compound as a waxy solid. Mass spectrum (m/e) (M+H) 358.1113. found (M+H) 358.1129.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]1[NH:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]=1[C:12](=O)[CH2:13][CH3:14].C(N)=N.C([O-])(=O)C.[NH4+]>>[CH2:13]([C:12]1[N:2]=[CH:3][CH:4]=[C:5]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:11])[NH:10]2)[CH3:14]
Reactant: CCC(=O)c1ccc(=O)[nH]c1C=CN(C)C
Agent: CC(=O)[O-]
Agent: N=CN
Agent: [NH4+]
Product: CCc1nccc2[nH]c(=O)ccc12

Procedure:
The process according to claim 12 which comprises reacting 6-(2-dimethylaminoethenyl)-5-(n-propanoyl)-2(1H)-pyridinone with formamidine or ammonium acetate to produce 5-ethyl-1,6-naphthyridin-2(1H)-one.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][CH:21]=1.CC#N>O=S(Cl)Cl.CN1C(=O)CCC1>[N:20]1[CH:25]=[CH:24][C:23]([NH:26][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[O:19])=[N:22][CH:21]=1
Reactant: Nc1ccncn1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Solvent: CN1CCCC1=O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccncn1)c1cn(Cc2ccccc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
1-Benzylindole-3-carboxylic acid (25.9 mg, 96 mmol) was dissolved in SOCl2 (1 mL) and the mixture was stirred for 30 min before the volatiles were removed in vacuo. The residue was dissolved in MeCN (200 μL) and added to a solution of pyrimidin-4-yl-amine (10 mg, 105 mmol) in NMP (200 μL). The reaction mixture was stirred 16 hours at room temperature before the MeCN was removed in vacuo. The residue was purified using HPLC method D to give title compound. HPLC-MS (Method A): m/z=329 (M+1); Rt=3.3 min.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[CH2:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1.C1C=CC2N(O)N=NC=2C=1.N=C=N>CN(C=O)C>[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH2:21][N:22]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:10]=2)=[O:35])=[CH:32][CH:31]=1)[CH2:23][C:24]1[NH:28][CH:27]=[CH:26][N:25]=1
Reactant: CCCN(CCC)Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1cccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The compound (51.6 mg) obtained in Example 33-2, the compound (117 mg) obtained in Example 2-2, and HOBt (50.0 mg) were dissolved in anhydrous DMF (2.5 ml). Then, the solution was added with PS-carbodiimide (manufactured by Argonaut Technologies, Inc.) (373.1 mg), followed by stirring at room temperature for 17 hours. After completion of the reaction, the mixture was filtrated and the solvent was then distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution. The residue was dried with anhydrous magnesium sulfate and the solvent was distilled off, followed by treatment with hydrochloric acid. The residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (18.5 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24]C)[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18].O1CCCCC1CCN1C(=O)CSC1CCCCCCC(OC)=O>>[O:1]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:2]1[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCCC(O)CCN1C(=O)CSC1CCCCCCC(=O)OC
Agent: COC(=O)CCCCCCC1SCC(=O)N1CCC1CCCCO1
Product: O=C(O)CCCCCCC1SCC(=O)N1CCC1CCCCO1

Procedure:
This compound is prepared essentially by the same method as described in Example 1, Step C, except that the methyl 7-[3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl]heptanoate is replaced by methyl 7-{3-[2-(tetrahydro-2H-pyran-2-yl)-ethyl]-4-oxo-2-thiazolidinyl}heptanoate. After careful chromatographic purification on silica gel, the title compound is obtained as a viscous, pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[C:20]1[C:21](=[O:46])[N:22]([CH3:45])[CH:23]=[C:24]([C:26]2[C:27]([CH3:44])=[C:28]([NH:32][C:33]([C:35]3[S:39][C:38]4[CH2:40][CH2:41][CH2:42][CH2:43][C:37]=4[CH:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:13][N:11]([CH3:12])[C:9](=[O:10])[C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20]2[C:21](=[O:46])[N:22]([CH3:45])[CH:23]=[C:24]([C:26]3[C:27]([CH3:44])=[C:28]([NH:32][C:33]([C:35]4[S:39][C:38]5[CH2:40][CH2:41][CH2:42][CH2:43][C:37]=5[CH:36]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)[N:25]=2)=[CH:3][CH:4]=1)[N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15]
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Br)n1
Reactant: CC(C)N(C)[C@H](C(=O)N(C)C)c1ccc(N)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc([C@@H](C(=O)N(C)C)N(C)C(C)C)cc2)n1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
A 15-mL three-neck round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was charged with 23 (53 mg, 0.212 mmol), 11 (98 mg, 0.212 mmol), cesium carbonate (152 mg, 0.468 mmol) and 1,4-dioxane (3 mL). After bubbling nitrogen through the resulting solution for 30 minutes, Xantphos (10.4 mg, 0.018 mmol) and tris(dibenzylideneacetone)dipalladium(0) (9.70 mg, 0.010 mmol) were added and the reaction mixture was heated at reflux for 3 h. After this time the reaction was cooled to room temperature, filtered and the filter cake washed with methylene chloride (2×25 mL). The filtrate was then concentrated under reduced pressure and the residue was purified by column chromatography to afford 24 (68 mg, 52%) as a yellow solid: mp 133-134° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.79 (br s, 1H), 9.19 (br s, 1H), 7.93 (d, 2H, J=8.5 Hz), 7.68 (s, 1H), 7.30 (m, 5H), 7.20 (s, 1H), 4.56 (s, 1H), 3.55 (s, 3H), 3.01 (s, 3H), 2.84 (m, 1H), 2.76 (m, 5H), 2.63 (t, 2H, J=5.5 Hz), 2.28 (s, 3H), 2.02 (s, 3H), 1.79 (m, 4H), 0.91 (m, 6H); MS (ESI+) m/z 627.5 (M+H); [α]25D+24.0° (c 0.25, chloroform).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Cl)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:27][O-:28].[Na+]>CO>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([O:28][CH3:27])[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C[O-]
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: COc1nc2cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(Br)c2s1
Yield: 79 %

Procedure:
The reaction mixture of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (65I) (90 mg, 0.195 mmol), NaOMe in MeOH (25% wt, 66 ul) in MeOH (3 ml) was heated at 50° C. for 20 min in sealed microwave vial. The reaction mixture was washed by sat. NaHCO3, extracted by EtOAc, dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65J (70 mg, 79%).
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[Cl:24])=[O:33])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:18][CH2:19][S:20](=[O:23])[CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Reactant: O=C=Nc1ccccc1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)CC2)c1O
Yield: 43.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-2-hydroxy-3-(1-oxidothiomorpholinosulfonyl)aniline (117 mg, 0.35 mmol) and 2-chlorophenylisocyanate (58 mg, 0.28mmol) were coupled to form the desired urea (58 mg, 35%). LC-MS (m/z) 478.0 (M+).
Reaction SMILES: C(OC([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](CCOS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1C)=O)C1C=CC=CC=1.COC[C@@H]1CCC[NH:32]1>O1CCOCC1>[NH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:12]1[NH2:32]
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: COC[C@@H]1CCCN1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2[nH]1
Yield: 168.1 %

Procedure:
5-(2-Methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (0.350 g, 0.900 mmol, 1 eq, Example 56, Step D) was suspended in dioxane (20 mL) under Ar. (S)-2-(Methoxymethyl)-pyrrolidine (0.207 g, 1.800 mmol, 2 eq) was added. The reaction mixture was stirred and heated to reflux for 18 hours. Then the reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic phases were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed, eluting with ethyl acetate/methanol/triethyl amine (100/10/1). 0.200 g (55%) of the indole-amine was obtained as a white solid. This was converted to the HCl salt. LC/MS (ESI+) 407 (M+1); Anal. Calcd for C25H30N2O3.1HCl.1H2O: C, 65.14; H, 7.22; N, 6.08; Found: C, 65.48; H, 7.14; N, 6.04.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[NH2:12][NH2:13].C(OCC)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: CCOC(=O)c1ccccn1
Solvent: CCOCC
Solvent: CCO
Product: NNC(=O)c1ccccn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl pyridin-2-carboxylate (90 gm) and hydrazine (60 gm) in ethanol (400 ml) was stirred at 80° C. over a period of 4 h. Solvent was evaporated and to provide a crude mass. The mass was stirred with diethyl ether and the suspension was filtered and the wet cake washed with small quantity of ethanol (50 ml) to provide title compound in 76 gm quantity (93%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:35]4[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:29]#[N:30])[CH:3]=3)[O:8][CH:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:28])[F:27])=[CH:20][CH:19]=3)[CH2:10]2)[N:12]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(c3ccc(OC(F)(F)F)cc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(c3ccc(OC(F)(F)F)cc3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 2.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.11 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3-cyanophenylboronic acid (32.4 mg, 0.22 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure 3-(3′-amino-2′-methyl-2-(4-(trifluoromethoxy)phenyl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (1.39 mg, 5%). 1H-NMR (MeOD): 2.34 (t, 1H), 2.89 (d, 1H), 5.41 (t, 1H), 7.13 (d, 1H), 7.37 (t, 2H), 7.64 (m, 3H), 7.70 (d, 1H), 7.78 (t, 1H), 7.94 (t, 1H), 8.04 (m, 2H).