Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:11]1[S:15][CH:14]=[C:13]([C:16]#[N:17])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]O)#[N:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][CH:34]=1)[O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:19]>>[C:1]([C:3]([C:11]1[S:15][CH:14]=[C:13]([C:16]#[N:17])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][O:23][C:22]2[CH:32]=[CH:33][CH:34]=[C:20]([C:18]#[N:19])[CH:21]=2)[CH2:31][CH2:30]1)#[N:2]
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCO)c1cc(C#N)cs1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1cc(C#N)cs1

Procedure:
The title compound was obtained as a pale yellow oil (0.15 g, 58%) from 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanol and 1-[2-(3-cyanophenoxy)ethyl]piperazine in the same manner as in Example 68.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([C:31](N)=[O:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[OH-:34].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:30][C@H:29]([C:31]([OH:32])=[O:34])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: [OH-]
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](C(N)=O)C1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1C[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
This compound was prepared utilizing the same procedures as those used for the synthesis of cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanecarboxylic acid amide except the reaction was monitored at short intervals to minimize the amide formation. The reaction generated a mixture of ester and amide (2:1), which was treated with NaOH (0.15 mL) in THF (0.95 mL) and MeOH (1 mL). The reaction was left to stir at rt for 3 h. The mixture was concentrated in vacuo, diluted with DCM and washed with water. The product was purified by MDP, to afford the title compound as a yellow solid; MS (ES+): m/z 436.27 (40) [MH+]; 1H NMR (400 MHz, DMSO-d6) δ 2.62-2.67 (m, 5H) 3.16 (s, 1H) 3.90-3.91 (m, 1H) 6.21 (s, 1H) 7.10 (d, J=5.2 Hz, 1H) 7.50-7.59 (m, 4H) 7.93 (dd, J=6.8, 1.6 Hz, 1H) 8.10 (d, J=8.4 Hz, 1H) 8.18 (d, J=8.8 Hz, 1H) 8.25 (s, 1H) 8.30-8.33 (m, 2H) 8.51 (d, J=8.4 Hz, 1H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Cl-].[Mg+2].[Cl-]>[Co](Cl)Cl>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl[Co]Cl
Agent: [Cl-]
Agent: [Mg+2]
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Two series of four glucose-containing liquor samples (mother liquor from primary dextrose crystallization, 90DE) were prepared containing 0.005M magnesium chloride and 0.001M cobalt chloride. Series A contained 53.4 percent dry substance, and Series B contained 56.7 percent dry substance. To the samples, were added various quantities of the air-dried filter cake of example I and sulfite salts. The isomerizations were carried out at 70° C. for various times under an atmosphere of nitrogen. The color and fructose formed during the isomerization reactions were determined and are shown below in table III.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]1([N:19]2[C:24]3=[N:25][C:26](S(C)=O)=[N:27][CH:28]=[C:23]3[CH2:22][NH:21][C:20]2=[O:32])[CH2:18][CH2:17][CH2:16][CH2:15]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O1CCOCC1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH:14]1([N:19]2[C:24]3=[N:25][C:26]([NH:1][C:2]4[CH:3]=[CH:4][C:5]([N:8]5[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]5)=[CH:6][CH:7]=4)=[N:27][CH:28]=[C:23]3[CH2:22][NH:21][C:20]2=[O:32])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CS(=O)c1ncc2c(n1)N(C1CCCC1)C(=O)NC2
Reactant: Nc1ccc(N2CCCCC2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C1NCc2cnc(Nc3ccc(N4CCCCC4)cc3)nc2N1C1CCCC1
Yield: 24 %

Procedure:
A solution of 377 mg (2.14 mmol) of 1-(4-aminophenyl)piperidine, 300 mg (1.07 mmol) of 1-cyclopentyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, 745 mg (3.21 mmol) of camphorsulfonic acid, and 2 mL of p-dioxane is heated at 130° C. for 1 hour in a sealed tube. The mixture is cooled and diluted with chloroform. The solution is washed twice with saturated aqueous sodium bicarbonate and once each with aqueous sodium chloride then brine. The organic phase is dried over magnesium sulfate and concentrated to leave a dark green residue that is dissolved in chloroform and chromatographed on silica gel eluting with 9:1:0.5 ethyl acetate/ethanol/triethylamine. The product fractions are pooled and concentrated to leave a residue that is dissolved in chloroform. The solution is diluted with ethyl acetate while most of the chloroform is being boiled away. Upon cooling, crystals form and are then collected to leave 101 mg (24%) of the title compound:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:9]=2[C:10]=1[CH2:11][N:12]=[N+]=[N-])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:9]=2[C:10]=1[CH2:11][NH2:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1CN
Temperature: 70 °C
Yield: 32.7 %

Procedure:
3-Azidomethyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester (49 mg) and triphenylphosphine (50 mg) were dissolved in THF (2.5 ml). To the solution was added water (0.3 ml) and the mixture was heated to 70° C. overnight. The reaction mixture was diluted with ethyl acetate (5 ml) and washed with brine (5 ml), then dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography developed by dichloromethane-methanol giving 3-aminomethyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester as a colorless oil (15 mg). FAB-MS: m/z 384 (MH+); 1H-NMR (CDCl3): δ 1.45 (3H, t, J=7.3 Hz), 2.12 (2H, quintet, J=6.3 Hz), 2.90 (2H, t, J=6.6 Hz),3.85 (2H, s), 4.24 (2H, t, J=6.3 Hz), 4.31 (2H, s), 4.45 (2H, q, J=7.3 Hz), 6.68 (1H, d, J=8.3 Hz), 7.16 (1H, d, J=8.3 Hz), 7.21 (1H, dd, J=4.9 Hz, 7.9 Hz), 7.35 (1H, t, J=8.3 Hz), 7.68 (1H, d, J=7.9 Hz), 8.48 (1H, dd, J=1.7 Hz, 4.9 Hz), 8.56 (1H, d, J=1.7 Hz).
Reaction SMILES: C[N:2]([CH3:30])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:16]3[C:24]4[C:19](=[CH:20]C=C(NC=O)[CH:23]=4)[NH:18][C:17]3=[O:28])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:29].F[C:32]([F:37])(F)[C:33](O)=O.Cl[CH2:39]Cl>>[CH2:30]([NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:16]3[C:24]4[C:19](=[CH:20][CH:33]=[C:32]([F:37])[CH:23]=4)[NH:18][C:17]3=[O:28])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:29])[CH3:39]
Reactant: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Product: CCNCCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A stirred solution of ethyl-{2-[2-(6-fluoro-2-oxo-indan-1-ylidenemethyl)-3-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl]-ethyl}-carbamic acid tert-butyl ester (1.2 g, 2.5 mmol) obtained from Example 116 in dichloromethane (25 ml) was added dropwise slowly with 2.5 ml of trifluoroacetic acid. Upon the completion of the addition, the mixture was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure to give 5-(2-ethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (0.94 g, 98%) as a yellow solid.
Reaction SMILES: C=C.[C:3]1([CH2:9][C:10]([NH:12][C@@H:13]2[C:40](=[O:41])[N:15]3[C:16]([C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)=[O:29])=[C:17](OS(C(F)(F)F)(=O)=O)[CH2:18][S:19][C@H:14]23)=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:42](N(C(C)C)CC)(C)[CH3:43]>C(OCC)(=O)C>[O:41]=[C:40]1[N:15]2[C@H:14]([S:19][C@@H:18]3[C:17](=[C:16]2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])[CH2:43][CH2:42]3)[C@@H:13]1[NH:12][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: C=C
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)C2=C3CC[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reaction time: 18 h
Yield: 60.6 %

Procedure:
Ethylene was bubbled into a solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethanesulphonyloxy)ceph-3-em-4-carboxylate (0.50 g, 0.852 mmol) in ethyl acetate (500 ml) whilst a solution of diisopropylethylamine (0.15 ml, 0.852 mmol) in ethyl acetate (100 ml) was added dropwise over 2 h. After completion of the addition the mixture was left to stand for 18 h then the solvent was evaporated under reduced pressure. The residue was chromatographed to give the title compound (0.24 g, 61%), (Found: M+, 464.1411. C25H24N2O5S requires M, 464.1406); νmax (CH2Cl2) 1786, 1722, 1686, 1604 cm-1 ; δH (CDCl3) 2.08 (1H, m), 2.46 (1H, dtd, J 10.4, 9.3, 3.2), 3.16 (1H, dtd, J 15.8, 9.4, 1.6), 3.28 (1H, ddt, J 15.8, 8.8, 3.0). 3.63 (2H, ABq, J 16.1), 3.80 (3H, s), 4.32 (1H, dddd, J 9.3, 8.2, 2.8, 1.5), 4.94 (1H, d, J 5.0), 5.18 (2H, ABq, J 11.9), 5.76 (1H, d, J 8.8, 5.0), 5.97 (1H, d, J 8.8), 6.87 (2H, d, J 8.7), 7.26 (7H, m).
Reaction SMILES: O=S(Cl)Cl.CN([CH:8]=[O:9])C.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].C[CH2:22][O:23][C:24]([CH3:26])=[O:25]>C(Cl)Cl>[CH3:22][O:23][C:24]([C@@H:26]1[CH2:13][CH2:12][CH2:11][C@@H:16]1[C:8](=[O:9])[C:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:25]
Reactant: CCOC(C)=O
Reactant: Brc1ccccc1
Reactant: CN(C)C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1CCC[C@@H]1C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A solution of the monomethyl ester (92.0 g, 534.3 mmol), SOCl2 (116.3 mL, 1.60 mol), and DMF (1 mL) in 850 mL CH2Cl2 was stirred at rt overnight under N2. NMR analysis showed little starting material remaining. The solvent was removed by rotary evaporation at <40° C., and the residue was dried in vacuo for 1 h. This dried residue was dissolved in bromobenzene (337.6 mL, 3.2 mol), and AlCl3 (142.5 g, 1.07 mol) was then added portionwise at <5° C. The reaction mixture turned dark brown, and was stirred at <5° C. for 4 h under N2. NMR analysis then showed little starting material remaining. The reaction mixture was then slowly poured into 2 L ice-water, and then 1 L EtOAc was added. After the mixture was stirred for 10 minutes, the aqueous (top) layer was separated, and extracted with 500 mL EtOAc. The combined organic layers were washed with water (2×1 L) and saturated NaHCO3 solution (200 mL), and dried over Na2SO4. Removal of solvent and drying in vacuo provided 175.0 g (>95%) of the desired product. 1H NMR (CDCl3) δ 7.80 (d, 2H), 7.60 (d, 2H), 4.07 (m, 1H), 3.53 (s, 3H), 3.07 (m, 1H), 2.20 (m, 1H), 2.00 (m, 4H), 1.70 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[NH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[N:11]([CH3:20])[C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:14]=1
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(C(F)(F)F)cnc(-c2ccc(Cl)cc2Cl)c1=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 64.6 %

Procedure:
First, 1.20 g of 3-(2,4-dichlorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1007) was dissolved in 6.0 ml of N,N-dimethylformamide, to which 0.83 g of potassium carbonate and 0.51 ml of methyl iodide were added, and the mixture was stirred at 100° C. for 2 days. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=5:1), which afforded 0.81 g (yield, 62%) of 3-(2,4-dichlorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-332).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])[CH:5]=[CH:4][N:3]=1.[CH3:45][O-:46].[Na+]>CO>[CH3:45][O:46][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@H:11]([S:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[F:44])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ccnc(Cl)n2)cc1F
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COCc2cc(F)c(F)cc2F)n1
Temperature: 75 °C
Yield: 77 %

Procedure:
A solution of 0.24 (0.4 mmol) (2S,4R)-2-Chloro-4-[2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine in 1 ml MeOH was treated at 0° C. with 0.16 ml (0.88 mmol) sodium methylate (5.5 M in MeOH) and kept at this temperature (2 h), warmed up and heated for 10 h at 75° C. After evaporation and extraction with aqueous saturated NH4Cl/Et2O (3×), the organic phases were washed with aq. 10% NaCl, dried (Na2SO4) and evaporated to give 0.19 g (77%) 2-Methoxy-4-[(2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine, MS: 628 (MH+), which was deprotected (see General method for S-deprotection, Method D) to give (3R,5S)-1-(2-Methoxy-pyrimidin-4-yl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol, MS: 386 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.N([O-])=O.[Na+].[N-:13]=[N+:14]=[N-].[Na+]>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1)=[N+:13]=[N-:14]
Reactant: Nc1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
5-Amino-2-chloropyridine (2.28 g; 17.7 mmol; 1.0 eq.) was dissolved in TFA (7 mL). Sodium nitrite (1.35 g; 19.5 mmol; 1.1 eq.) was then added portion wise to this solution maintained at 0° C. Reaction mixture was stirred at 0° C. for 30 min before the addition of and ice-cold solution of sodium azide (1.15 g; 17.7 mmol; 1.0 eq.) in water (8 mL). It was stirred at 0° C. for 1 h. TFA was then removed and the residue was dissolved in EtOAc. Organic phase was washed with an aqueous saturated solution of NaHCO3, brine, dried over magnesium sulfate, filtered and concentrated. The crude obtained was purified by flash chromatography on silica (heptane:EtOAc, gradient from 95:5 to 80:20) to afford the title compound as a brown oil (1.89 g, 69%). 1H NMR (300 Mz, DMSO-d6) δ 8.23 (dd, J=0.6, 2.9 Hz, 1H), 7.68 (dd, J=2.9, 8.6 Hz, 1H), 7.54 (dd, J=0.6, 8.6 Hz, 1H).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.Cl.[CH3:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1>>[ClH:6].[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH2:22][CH2:21][CH2:20][N:19]=1
Reactant: Cc1cc(N)ccc1NC1=NCCC1
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)Nc1ccc(NC2=NCCC2)c(C)c1

Procedure:
The title compound was prepared by the method of Example 21 using 30.5 mmole of butanoyl chloride and 1.0 g (3.8 mmole) of the product compound of Example 9. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19].[CH3:22]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:22])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro-3-isobutyrylox-10H-phenothiazine (see Example 8) (202 mg) in DMF (5 ml) was added methyl iodide (0.2 ml) and sodium hydride (18 mg) at 0° C. The reaction mixture was stirred at ambient temperature for 12 hours. To the reaction mixture was added water and the resulting aqueous layer extracted with EtOAc. The organic layers were collected, dried and evaporated to give a residue which was purified by chromatography on silica gel (plates) to give 100 mg of 4-chloro-3-isobutyryloxy-10-methyl-10H-phenothiazine (m.p. 147° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:39]=[CH:40][C:41]=1[CH3:42])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1)=[O:19])#[CH:14]>>[CH3:42][C:41]1[CH:40]=[CH:39][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)=[C:23]([C:35]([F:36])([F:38])[F:37])[CH:22]=2)=[O:19])=[CH:16][C:15]=1[C:13]#[C:14][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Reactant: Brc1ccc(-c2nc[nH]n2)nc1
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(-c2nc[nH]n2)nc1

Procedure:
The title compound was prepared using 5-bromo-2-(1,2,4-triazol-3-yl)pyridine and 3-ethynyl-4-methyl-N-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]benzamide as raw materials, according to the method described in Step 4 of Example 3.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:20]([O-:22])=[O:21])[C:10]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:25].O1[CH2:30][CH2:29][CH2:28][CH2:27]1>CO.CS(C)=O>[Cl:25][C:28]1[C:29]([CH3:30])=[C:19]([CH2:11][N:12]2[C:11]3[CH:19]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=[C:9]([C:20]([OH:22])=[O:21])[C:10]=3[N:14]=[C:13]2[C:15]([F:17])([F:16])[F:18])[CH:7]=[CH:8][CH:27]=1
Reactant: O=C([O-])c1cc(N2CCOCC2)cc2[nH]c(C(F)(F)F)nc12
Reactant: C1CCOC1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1c(Cl)cccc1Cn1c(C(F)(F)F)nc2c(C(=O)O)cc(N3CCOCC3)cc21
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A suspension of methyl 1-[3-chloro-2-methylphenyl)methyl]-6-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-4-carboxylate, prepared as described in Example 49 (1.09 g, 2.330 mmol) in Methanol (12 mL) and Tetrahydrofuran (THF) (4 mL) was treated with 1 M aq. sodium hydroxide (12 mL, 12.00 mmol) and stirred at 70° C. for 1.5 h (mixture turned homogeneous). The reaction was cooled to room temperature, the volume reduced to half and the residue was acidified (pH 4) by the addition of 1 N HCl. The precipitate was collected, washed with water and dried to give crude desired product (918.6 mg, 2.024 mmol, 87% yield) as a yellow solid. A portion of it (140 mg) was suspended in 3.5 mL of DMSO. After sonication and heating, the solid went into solution but it crashed out. The precipitate was collected and washed with DMSO, but it still showed impurities by LC/MS. Another aliquot (132 mg) was dissolved with heating in 5 mL of DMSO and purified by reverse phase-HPLC (15 to 95% AcCN in water plus 0.1% TFA). The desired product was isolated by evaporation of the organic solvent: the precipitate was collected by filtration, washed with water and dried in a vacuum oven to afford pure desired product (89 mg, 0.192 mmol, 8.25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (s, 1H), 7.63 (d, J=2.27 Hz, 1H), 7.36 (d, J=7.83 Hz, 1H), 7.30 (d, J=2.27 Hz, 1H), 7.05 (t, J=7.96 Hz, 1H), 5.98 (d, J=7.58 Hz, 1H), 5.70 (s, 2H), 3.66-3.83 (m, 4H), 3.08-3.24 (m, 4H), 2.47 (s, 3H). MS (ES+) m/e 453.9 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([N:5]2[CH2:10][C:9]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[O:8][CH2:7][C:6]2=[O:16])[CH2:4][CH2:3]1.[OH-].[Na+].O.O=[CH:21][C:22]([OH:24])=[O:23].[Br:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>ClCCl>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH:21]([N:13]2[CH2:12][CH2:11][C:9]3([O:8][CH2:7][C:6](=[O:16])[N:5]([CH:2]4[CH2:4][CH2:3]4)[CH2:10]3)[CH2:15][CH2:14]2)[C:22]([OH:24])=[O:23])=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: O=CC(=O)O
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Reaction time: 1 h
Yield: 18 %

Procedure:
A suspension of 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (8.11 mmol) in dichloromethane (20 mL) was treated with 1N aq sodium hydroxide (10 mL) at room temperature. After stirring for one hour, the dichloromethane layer had turned clear. The mixture was transferred to a separatory funnel and the organic phase was removed. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was dissolved in dichloromethane (20 mL) and treated with 2-oxoacetic acid monohydrate (8.11 mmol) and (4-bromophenyl)boronic acid (8.11 mmol) at room temperature. The reaction was allowed to stir at room temperature for 4 days, at which point an additional equivalent of 2-oxoacetic acid monohydrate (8.11 mmol) was added. The reaction was allowed to stir overnight, at which point the suspension was concentrated in vacuo. Purification of the residue by reverse phase HPLC (5-30% acetonitrile/water with 0.1% NH4OH) afforded the title compound as a white solid (18%). MS(ES)+ m/e 422.9/424.8 [M+H]+ (bromide isotope pattern).