Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH:11]([F:13])[F:12])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.BrC1[C:16](OC(F)F)=[N:17][CH:18]=C(C)C=1.BrN1C(=O)CCC1=O.[N:34](C(C)(C)C#N)=[N:35]C(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.O>[N:34]1([CH2:8][C:6]2[CH:7]=[C:2]([Br:1])[C:3]([O:10][CH:11]([F:13])[F:12])=[N:4][CH:5]=2)[CH:18]=[N:17][CH:16]=[N:35]1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: Cc1cnc(OC(F)F)c(Br)c1
Reactant: FC(F)Oc1ncc(CBr)cc1Br
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)Oc1ncc(Cn2cncn2)cc1Br
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
3-Bromo-5-(bromomethyl)-2-(difluoromethoxy)pyridine. To a solution of 3-bromo-2-(difluoromethoxy)-5-methylpyridine (0.50 g, 2.1 mmol) in carbon tetrachloride (13 mL), was added 1-bromopyrrolidine-2,5-dione (0.521 g, 2.93 mmol), and azobisisobutyronitrile (44 mg, 0.26 mmol). The reaction mixture was stirred at 80° C. for 8 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 10-90%, EtOAc/hexanes) afforded the title compound (400 mg, 60%). [M+H]=317.88.
Reaction SMILES: [OH:1][CH:2]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([OH:14])=[O:13])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:15][Si:16]([CH:19]=[N+]=[N-])([CH3:18])[CH3:17]>ClCCl>[OH:1][CH:2]([C:7]1[O:8][CH:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)CC(O)c1occc1C(=O)O
Solvent: ClCCl
Product: CC(C)CC(O)c1occc1C(=O)OC[Si](C)(C)C
Reaction time: 20 h

Procedure:
2-(1-Hydroxy-3-methylbutyl)furan-3carboxylic acid (800 mg) was dissolved in dichloromethane (30 ml) an d a solution of trimethysilyldiazomethane (2M in hexane, 2.1 ml) was added. The mixture was stirred for 20 h, then diluted with dichloromethane and washed twice with hydrochloric acid. The organic phase was washed with brine, then dried, filtered and evaporated. Chromatography, eluting with diethylether:isohexane (1:1), gave the sub-title compound (435 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:24]=[C:23](Cl)[N:22]=[C:21](Cl)[N:20]=1)=[O:17])(=[O:14])=[O:13])(=O)C.[CH3:27][O-:28].[Na+].[CH3:30][OH:31]>>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][C:19]1[N:20]=[C:21]([O:28][CH3:27])[N:22]=[C:23]([O:31][CH3:30])[N:24]=1)=[O:17])(=[O:13])=[O:14]
Reactant: CC(=O)OCc1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)nc(Cl)n1
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2CO)nc(OC)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The crude 2-(acetoxymethyl)-N-[(4,6-dichloro-1,3,5-triazinyl)aminocarbonyl]benzenesulfonamide was treated with methanol (10 ml) and then with a solution of sodium methoxide (14 mmol) in methanol. The mixture was stirred at room temperature for 1.5 hour and evaporated. The residue was taken up in water and filtered. The filtrate was acidified and filtered to give 0.45 g of gummy solid which was recrystallized from a chloroform/acetone mixture to give 115 mg of white solid, m.p. 146°-148°(dec.). 'H NMR δDMSO-d6 12.2(brd s, 1H), 10.73 (s, 1H), 8.00-7.15 (m,4H), 4.80 (s and ~4.9-4.2 (brd s), 3H) 3.90 (s, 6H), consistent with the assigned structure.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][C:14]1[O:15][C:16]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][C:17]=2[CH:18]=1.[NH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2>>[NH:29]1[C:30]2[C:26](=[C:25]([NH:24][C:2]3[C:3]4[CH:4]=[CH:5][C:6]([NH:23][C:22]5[C:16]6[O:15][C:14]([CH3:13])=[CH:18][C:17]=6[CH:19]=[CH:20][CH:21]=5)=[N:7][C:8]=4[CH:9]=[CH:10][CH:11]=3)[CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28]1
Reactant: Cc1cc2cccc(N)c2o1
Reactant: Clc1ccc2c(I)cccc2n1
Reactant: Nc1cccc2[nH]ccc12
Product: Cc1cc2cccc(Nc3ccc4c(Nc5cccc6[nH]ccc56)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=405.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-iodo-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl)amine and 4-aminoindole.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2([CH3:31])[CH2:29][CH2:28][O:27][C:26]2=[O:30])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:26](=[O:30])[C:25]([S:22]([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)(=[O:24])=[O:23])([CH3:31])[CH2:29][CH2:28][OH:27])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC1(S(=O)(=O)c2ccc(Cl)cc2)CCOC1=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)C(C)(CCO)S(=O)(=O)c2ccc(Cl)cc2)no1
Reaction time: 0.25 h
Yield: 4.5 %

Procedure:
To a solution of 5-tert-butyl-isoxazol-3-ylamine (0.280 g; 2.00 mmol) in methylene chloride (5 mL) was added dropwise trimethylaluminum (1.0 mL of a 2.0 M solution in toluene; 2.00 mmol). The mixture was stirred 15 minutes and 3-(4-chloro-benzenesulfonyl)-3-methyl-dihydrofuran-2-one (0.440 g; 1.60 mmol) added. The mixture was stirred 18 hours and carefully quenched with 10% aqueous citric acid, aqueous sodium tartrate and chloroform. The organic layer was dried (MgSO4). Removal of the volatiles in vacuo provided a residue which was purified by silica gel chromatography using ethyl acetate and hexanes as the eluent. Removal of the volatiles from the product-rich fractions provided 0.030 g of the desired product. 1H NMR (CDCl3) δ 9.4 (bs, 1H), 7.76 (d, 2H), 7.52 (d, 2H), 6.49 (s, 1H), 3.90 (m, 1H), 3.82 (m, 1H), 2.58 (m, 1H), 2.25 (m, 1H), 1.65 (s, 3H), 1.3 (s, 9H). MS (ESI): m/e 415, 417 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1([CH:27](N(CCOC)C)[CH:28](N2C3C=CC=CC=3N=N2)[N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH3:30])C2C=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[C:14]([Br:15])=[CH:13][N:12]2[C:28]([N:29]([CH2:31][CH2:32][O:33][CH3:34])[CH3:30])=[CH:27][N:16]=[C:11]2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN(C)C(C(N(C)CCOC)n1nnc2ccccc21)n1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Product: COCCN(C)c1cnc2cc(CNC(=O)OC(C)(C)C)c(Br)cn12
Yield: 66 %

Procedure:
The cyclization was carried out as described for Example 6 from (2-amino-5-bromo-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (600 mg, 2.0 mmol, prepared according to Example 1, Step 1.3) and 1,2-bis-benzotriazol-1-yl-N,N′-bis-(2-methoxy-ethyl)-N,N′-dimethyl-ethane-1,2-diamine (871 mg, 2.0 mmol, prepared according to Example 6, Step 3.1). After the work-up, the crude was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME (containing 0.5% of a 7.0 M solution of NH3 in MeOH) 1:0→0:1) to yield the title compound (546 mg, 1.32 mmol, 67%) as a brownish oil. MS: 414 [M−1]+; HPLC: AtRet=1.40; TLC—RF 0.15 (hexane/DCM/TBME (containing 0.5% of a 7.0 M solution of NH3 in MeOH) 1:1:2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])=[C:4]([F:15])[CH:3]=1.[C:16]1(=O)[CH2:19][CH2:18][CH2:17]1.C[Si]([C:25]#[N:26])(C)C>C(OCC)(=O)C>[C:25]([C:16]1([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=[O:12])=[C:4]([F:15])[CH:3]=2)[CH2:19][CH2:18][CH2:17]1)#[N:26]
Reactant: C[Si](C)(C)C#N
Reactant: O=C1CCC1
Reactant: CNC(=O)CCCc1ccc(N)cc1F
Solvent: CCOC(C)=O
Product: CNC(=O)CCCc1ccc(NC2(C#N)CCC2)cc1F
Temperature: 80 °C
Reaction time: 15 h
Yield: 86.4 %

Procedure:
A mixture of 4-(4-Amino-2-fluorophenyl)-N-methylbutanamide (80) (8 mg, 0.04 mmol), cyclobutanone (5 mg, 0.08 mmol) and trimethylsilyl cyanide (TMSCN, 8 mg, 0.08 mmol) was heated to 80° C. and stirred for 15 h. To the medium was added ethyl acetate (2×20 mL) and then washed with water (2×20 mL). The organic layer was dried over MgSO4 and concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give 4-(4-(1-Cyanocyclobutylamino)-2-fluorophenyl)-N-methylbutanamide (79) (10 mg, 92%).
Reaction SMILES: C[O-].[Na+].CO[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[SH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7].[NH2:26][C@H:27]([C:29]([OH:31])=[O:30])[CH3:28].Cl>CO.O>[SH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][C@@H:27]([CH3:28])[C:29]([OH:31])=[O:30])=[O:7]
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1S)C(=O)O
Temperature: 150 °C

Procedure:
To a solution of 6.0 ml of 0.5 M sodium methoxide in methanol was added 100 mg of 4-Mercapto-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester and 286 mg of L-alanine. The mixture was heated to 150° C. for 15 minutes using a CEM Discover microwave reactor. The resultant solution was acidified to pH 3 with 1 N HCl, diluted with 10 ml water, and extracted with 20 ml of ethyl acetate. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated to 114 mg of product; MS (−): m/z 369.07 (M−1).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=2)[C:5](=[S:19])[N:4]([CH3:20])[C:3]1([CH3:22])[CH3:21].[O:23]1[CH2:27]CC[CH2:24]1>C(N(CC)CC)C>[CH3:21][C:3]1([CH3:22])[C:2](=[NH:1])[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:17])([F:16])[F:18])[CH:8]=2)[C:5](=[S:19])[N:4]1[CH2:20][CH2:24][OH:23].[C:11]([C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:5]([N:4]2[CH2:20][CH2:27][O:23][C:3]2([CH3:21])[CH3:22])=[S:19])=[C:14]([C:15]([F:18])([F:17])[F:16])[CH:13]=1)#[N:12]
Reactant: CN1C(=S)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=N)C1(C)C
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)C(=N)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1CCO
Product: CC1(C)OCCN1C(=S)Nc1ccc(C#N)cc1C(F)(F)F

Procedure:
A mixture of 1.18 g of the said mixture, 2.11 g of the isothiocyanate of Example 11 and 20 ml of tetrahydrofuran and 0.5 ml of triethylamine was refluxed for 30 minutes and then evaporated to dryness. The residue was chromatographed on silica and eluted with a 95-5 methylene chloride-acetone mixture to obtain 1.26 g of the desired product and 686 mg of N-(4-cyano-2-trifluoromethyl-phenyl)-2,2-dimethyl-3-oxazolidine carbothioamide. The 686 mg were dissolved in 10 ml of ethyl acetate and after the addition of 30 ml of cyclohexane, the mixture was concentrated to 4 ml and vacuum filtered and dried to obtain another 518 mg of product. The raw product was dissolved in 20 ml of isopropanol and the solution was concentrated to 5 ml, vacuum filtered and dried to obtain 1.04 g of the desired product melting at 181° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]3[CH2:19][C@@H:14]2[C:15]3([CH3:21])[CH3:20])(=O)=O)=CC=1.[C-:22]#[N:23].[K+]>CS(C)=O.[Cl-].[Na+].O>[CH3:21][C:15]1([CH3:20])[C@H:14]2[CH2:19][C@@H:16]1[CH2:17][CH2:18][C@@H:13]2[CH2:12][C:22]#[N:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)[C@H]2CC[C@H](CC#N)[C@@H]1C2
Temperature: 70 °C

Procedure:
To a solution of Example 21A (13.6 g, 44.2 mmol) in DMSO (100 mL) was added potassium cyanide (11.5 g, 177 mmol). The reaction was heated at 70° C. for 48 h. The mixture was diluted with brine and extracted with ether (3×75 mL). The organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on SiO2 (Hexanes/ethyl acetate, gradient 0 to 50%) to give the title compound.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([OH:34])[C@@H:20]([NH:30][C:31](=[O:33])[CH3:32])[CH2:21][C:22]2[CH:27]=[C:26]([O:28][CH2:2][CH:3]([CH3:5])[CH3:4])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C@@H:14]1[CH3:41])=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1cc(F)cc(OCC(C)C)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 55 %

Procedure:
Add 1-bromo-2-methyl-propane (0.05 g, 0.35 mmol) to (2R,3S,5R)-5-[(1S,2S)-2-acetylamino-3-(3-fluoro-5-hydroxy-phenyl)-1-hydroxy-propyl]-2-(2,2-dimethyl-propoxy)-3-methyl-morpholine-4-carboxylic acid tert-butyl ester (0.12 g, 0.23 mmol) and cesium carbonate (0.15 g, 0.46 mmol) in N,N-dimethylformamide (3 mL) under nitrogen and heat in a 60° C. oil bath for 2.5 hours. Cool to room temperature and dilute with ethyl acetate. Wash (0.1N citric acid, 10% potassium carbonate, saturated aqueous sodium chloride), dry (magnesium sulfate), filter and concentrate. Purify on 12 g silica gel column eluting with 100:0 to 40:60 hexanes:ethyl acetate to give 0.072 g (54.5%) of the title compound as a white foam.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(Cc2ccc(C)cn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-1-[(5-methylpyridin-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.42 g, 63%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([OH:30])(=[O:1])=[O:29].[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Agent: CCOc1ccc(C(=O)NCCCCO)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O
Temperature: 6 °C
Reaction time: 0.17 h

Procedure:
A 22-L, 3-necked, round-bottom flask equipped with a mechanical stirrer, nitrogen bubbler, and a thermocouple probe, was charged with 2.00 kg (8.43 mole) of N-(4-hydroxybutyl)-4-ethoxybenzamide (V-5), 2.94 L (2.18 kg, 16.85 mole, 2.00 eq) of diisopropylethylamine, and 11 L of DCM. The white slurry was cooled to 6° C., and 718 mL (1.062 kg, 9.27 mole, 1.10 eq) of methanesulfonyl chloride was added over a period of 1.5 h while maintaining a pot temperature of 5-12° C. with cooling. After stirring for 10 min at 5-10° C. the pale-brown solution was quenched into an extractor that contained 14 L of 1 N HCl. The phases were separated. The organic extract was washed with 14 L of 1 N HCl, washed with 9 L of saturated aq. NaHCO3, dried (MgSO4), filtered and concentrated (30° C., 50 mbar), to give, after air drying, 2.65 kg (99.7%) of N-(4-hydroxybutyl)-4-ethoxybenzamide methanesulfonate (V-6) as a pale-beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][C:13]=3F)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.C1OCCOCCOCCOCCOCC[O:21][CH2:20]1.C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][C:13]=3[O:21][CH3:20])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Cn1c(=O)c2cncc(F)c2c2ccc(Cl)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cncc2c(=O)n(C)c3cc(Cl)ccc3c12
Temperature: 100 °C
Yield: 973.3 %

Procedure:
To the solution of 8-chloro-1-fluoro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (40 mg, 0.152 mmol), prepared as described in Example 85, Part E, in MeOH (0.2 mL) in a microwave vial, 18-crown-6 (4.03 mg, 0.015 mmol) and sodium methoxide (32.9 mg, 0.152 mmol) in methanol were added and heated in a microwave oven at 100° C. for 30 min. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8-chloro-1-methoxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (40 mg, 0.146 mmol, 96% crude yield) as a white solid. The material was carried forward without further purification. LC/MS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12ClN2O2 275.05]; LC/MS retention time (method D): tR=0.72 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[Si]([N:41]=[C:42]=[O:43])(C)(C)C>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:30])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:42]([NH2:41])=[O:43])=[CH:27][CH:28]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1COCCO1
Product: NC(=O)Nc1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 70 °C

Procedure:
2-[4-(4-Amino-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (Compound 5050, Example 50, 40 mg, 0.095 mmol) was dissolved in 4 ml of 1:1 dioxane/TMS isocyanate. Reaction mixture was heated at 70° C. for 7 hours. It was then evaporated to dryness. The crude was redissolved in 10 ml of DMF and purified on reverse phase HPLC. MS: 466.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 12.39 (d, 1H), 7.72 (d, 2H), 7.42 (d, 3H), 7.35 (s, 2H), 7.10 (dd, 2H), 5.88 (br s, 2H), 5.02 (m, 2H), 4.50 (m, 1H), 2.25 (m, 2H), 1.90 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:12][C:13]([CH3:18])([CH3:17])[CH:14]([NH2:16])[CH3:15]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:16][CH:14]([CH3:15])[C:13]([CH3:18])([CH3:17])[CH3:12])=[S:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(N)C(C)(C)C
Reactant: N#Cc1cccc(N=C=S)c1
Solvent: C1CCOC1
Product: CC(NC(=S)Nc1cccc(C#N)c1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 3-cyanophenyl isothiocyanate (1.00 g, 6.24 mmol) in THF (25 mL) at room temperature was added (±) 3,3-dimethyl-2-aminobutane (1.08 mL, 9.36 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.2 g (78%) of 1-(3-cyanophenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[Li]CCCC.[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]=[O:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1.Cl>C1COCC1.O>[CH3:24][N:25]1[N:29]=[N:28][C:27]([C:30]2[CH:41]=[C:40]([CH3:42])[C:33]([O:34][CH2:35][CH2:36][CH2:37][CH:38]([C:11]3[NH:10][C:18]4[C:13]([CH:12]=3)=[CH:14][CH:15]=[CH:16][N:17]=4)[OH:39])=[C:32]([CH3:43])[CH:31]=2)=[N:26]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1cc2cccnc2[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 25.5 %

Procedure:
To a cold solution of 1-phenylsulfonyl-7-azaindole (1.29 g, 5 mmol) in 250 ml of THF was added at -30° C. n-BuLi (2.5M in hexane, 4 ml, 10 mmol). The mixture was stirred at -30°-40° C. for 1 h and then cooled to -50° C. To the above mixture was added dropwise at -50° C. a solution of 4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]butyraldehyde (1.37 g, 5 mmol) in 25 ml of THF, and the mixture was stirred at -40°-50° C. for 1 h and then allowed to warm to -50° C. for 2 h. Water was added to the mixture, and the resulting reaction mixture was acidified with 1N HCl solution, and then re-basified with an aqueous sodium bicarbonate solution, extracted with methylene chloride, and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/5-1/0; then methylene chloride/acetone 2/1-1/1) followed by recrystallization from methylene chloride/methanol to afford 501 mg (25%) of 2-[4-[4 -(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]1-hydroxy-butyl]-7-azaindole, as a white crystalline solid, m.p. 166°-169° C.