Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:17].N1C=CC=CC=1.[S:24]1[C:28]([C:29](Cl)=[O:30])=[CH:27][C:26]2[CH2:32][CH2:33][CH2:34][CH2:35][C:25]1=2>C(Cl)Cl>[CH3:1][C:2]1[C:7]([B:8]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:17][C:29]([C:28]1[S:24][C:25]2[CH2:35][CH2:34][CH2:33][CH2:32][C:26]=2[CH:27]=1)=[O:30]
Reactant: O=C(Cl)c1cc2c(s1)CCCC2
Reactant: Cc1c(N)cccc1B1OC(C)(C)C(C)(C)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
2-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (7) (1.20 g, 5.16 mmol, 1.0 equiv) and pyridine (0.42 mL, 25.8 mmol) are dissolved in DCM (40 mL) at 0° C. under a nitrogen atmosphere. 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8) (1.03 g, 5.16 mmol) is then added in portions over 5 min and allowed to react warming to RT over 60 min. All solvent is then removed under reduced pressure, and the resultant oil is reduced from toluene (3×20 mL) to remove residual pyridine. The residue is then dissolved in ethyl acetate and washed with sodium hydroxide (1N, 1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid [2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (9) as an off-white solid (1.87 g).
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:4]=1.S(Cl)([Cl:26])=O>>[Cl:11][C:9]([Cl:12])([Cl:10])[C:7]1[N:8]=[C:3]([C:2]([Cl:1])([Cl:22])[Cl:23])[N:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([Cl:26])=[O:18])=[CH:20][CH:21]=2)[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Product: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reaction time: 6 h

Procedure:
4-(4,6-Bis(trichloromethyl)-s-triazin-2-yl)-benzoic acid (87 pw) is added to thionyl chloride (350 pw). Upon heating to reflux in the absence of moisture and with vigorous stirring, a distinct evolution of SO2 can be observed. After 6 hours, a clear solution is present. Excess thionyl chloride is distilled, towards the end by applying a vacuum. The residue containing in virtually quantitative yield pure 4-(4,6-bis(trichloromethyl)-s-triazin-2-yl)benzoyl chloride is recrystallized from hexane, m.p. 100 to 101° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[Cl:10][C:11]1[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=1>C1COCC1.O.CCOC(C)=O>[Cl:10][C:11]1[N:12]=[N:13][C:14]([O:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[CH:15][CH:16]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-dimethylamino-propanol (95 μL) in 5 mL of THF at 0° C. was added NaH (20 mg). The mixture was stirred for 5 min; then 3,6-dichloropyridazine (100 mg) was added and the mixture was allowed to warm to room temperature and stirred overnight at this temperature. The mixture was diluted with 5 mL of water and 5 mL of EtOAc, the phases were separated, and the aqueous phase was extracted with 2×5 mL of EtOAc. The combined organics were washed with 5 mL of brine, dried over Na2SO4 and concentrated to a colorless oil (128 mg) that was used without further purification. Mass spectrum (ESI) 215.9 (M+).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C1N(C2CCCCC2)N=C(C)C=1)=O.[OH-].[Li+].C1(N2C(N3C[C@H](S(C4C=CC=CC=4C(F)(F)F)(=O)=O)C[C@@H]3C(O)=O)=CC(C)=N2)CCCCC1>>[CH:29]1([N:24]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])(=[O:11])=[O:12])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])=[CH:27][C:26]([CH3:28])=[N:25]2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCCCC1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCCCC1
Agent: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2C(=O)O)n(C2CCCCC2)n1
Agent: [Li+]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(C2CCCCC2)n1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give a mixture of the title compound and (2R,4R)-1-(2-cyclohexyl-5-methyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid as colorless solid which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[S:27][CH3:28])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[S:27]([CH3:28])=[O:38])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [4-(3-benzyloxy-2-methylsulfanylphenoxy)-butyl]-carbamic acid tert-butyl ester (600 mg, 1.44 mmol) in methylene chloride (15 mL) is added mCPBA (355 mg, 1.44 mmol) and the mixture is stirred at RT for 2 h. Water is added the organic phase is washed with saturated NaHCO3, water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:25]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:32]2[C:27]([N:28]([CH3:43])[C:29](=[O:42])[N:30]([CH3:41])[C:31]2=[O:40])=[CH:26]1)[CH2:4][S:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>C(Cl)Cl>[CH3:51][S:52]([O:1][CH2:2][C@H:3]([N:25]1[C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:32]2[C:27]([N:28]([CH3:43])[C:29](=[O:42])[N:30]([CH3:41])[C:31]2=[O:40])=[CH:26]1)[CH2:4][S:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:54])=[O:53]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CO)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](COS(C)(=O)=O)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-6-(1-Hydroxy-3-(tritylthio)propan-2-yl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 2) (2.5 g, 4.25 mmol) was dissolved in DCM (80 mL) and triethylamine (1.186 mL, 8.51 mmol) was added followed by methanesulfonyl chloride (0.398 mL, 5.10 mmol). The mixture was stirred at room temperature for 2 hours, further methanesulfonyl chloride was added and the mixture stirred for 50 mins. The reaction mixture was quenched with sat. NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc in iso-hexane gave the title compound.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:24])(=O)[CH3:2].Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:26]([O:28][NH:29][C:1](=[C:4]1[C:5](=[O:24])[CH2:6][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[CH2:8][C:9]1=[O:10])[CH3:2])[CH3:27]
Reactant: CCON
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.1 Grams of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of ethanol, and 0.71 g of ethoxyamine hydrochloride and 0.68 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. Chloroform was removed and the residue was purified by column chromatography on silica gel (eluent, ethyl acetate:hexane=1:5) to obtain 1.2 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione as white crystals.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:32])[C:7]([CH3:31])([CH3:30])[CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29].Cl>O.O1CCOCC1>[CH3:30][C:7]([CH3:31])([CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]2[C:20]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:10]1=[O:29])[C:6]([OH:32])=[O:5]
Reactant: COC(=O)C(C)(C)Cn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2scc(Cn3c(=O)n(CC(C)(C)C(=O)O)c4ccccc43)c12
Reaction time: 60 h
Yield: 91.8 %

Procedure:
Lithium hydroxide monohydrate (4.3 mg, 0.10 mmol) is dissolved in water (1.0 mL) and it is added into the solution of 2,2-Dimethyl-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid methyl ester (28 mg, 0.069 mmol) in 1,4-dioxane (2.0 mL) at room temperature. The mixture is stirred for 60 hr and LCMS then 1.0 M HCl solution (1.0 mL) is added followed by water (15 mL). Then the mixture is extracted with EtOAc (3×30 mL) and the organic layers are combined, dried over MgSO4 and concentrated to give 25 mg (90%) of 2,2-Dimethyl-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3dihydro-benzimidazol-1-yl]propionic acid. LCMS (ESMS): m/z 395.17 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)([CH3:10])[CH3:9])[C:5]([F:12])=[CH:4][CH:3]=1.CS(OS(C)(=O)=O)(=O)=O.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8]([CH3:10])=[CH2:9])[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1nc(Br)ccc1F
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)c1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of 2-(6-bromo-3-fluoro-pyridin-2-yl)-propan-2-ol (22.3 g, 95 mmol) and methanesulfonic acid anhydride (49.8 g, 286 mmol) in dichloromethane was added dropwise triethylamine (53.1 ml, 381 mmol) at 0° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was quenched with aq. sodium carbonate solution and diluted with dichloromethane. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo (volatile). The crude brown oil was chromatographed over silica (cyclohexane:ethyl acetate 9:1) to give the title compound as a clear liquid. 17.35 g (84% yield). TLC (cyclohexane/ethyl acetate 9:1) Rf=0.58; 1H-NMR (360 MHz, CDCl3): 7.26-7.15 (m, 2H), 5.72 (s, 1H), 5.47 (s, 1H), 2.12 (s, 3H, CH3).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:17]=1[C:18]([NH2:20])=[O:19].S(=O)(O)[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:16]2[C:17]=1[C:18](=[O:19])[NH:20][C:9]([C:8]1[CH:11]=[C:12]([CH3:13])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH3:14])[CH:7]=1)=[N:15]2
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: NC(=O)c1c(N)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3cccc(Cl)c3c(=O)[nH]2)cc(C)c1OCCO

Procedure:
4-(2-Hydroxyethoxy)-3,5-dimethylbenzaldehyde (0.70 g, 3.58 mmol), 2-amino-6-chlorobenzamide (0.60 g, 3.51 mmol), sodium bisulfite (0.71 g, 3.86 mmol) and p-toluenesulfonic acid monohydrate (0.133 g, 0.699 mmol) in anhydrous N,N-dimethyl acetamide (14 mL) were heated at 120° C. under nitrogen for 23 hours. The solvent was evaporated and the white solid was triturated with water (50 mL), filtered, and washed with water (20 mL). The solid was dried in vacuo and triturated with Et2O (20 mL), filtered, and dried to give 5-chloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one as a white solid. Yield: 0.77 g, (64%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12].Cl.CN(C)CCCN=C=NCC.N=C=N>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:14][CH2:13][CH2:11][OH:12])=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N=C=N
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCCO)cc1
Reaction time: 1 h

Procedure:
A solution of 4-aminobenzoic acid (2.7 g, 20 mmol), ethanolamine (1.4 g, 23 mmol), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (4.1 g, 21 mmol) in dimethylformamide (60 ml) was stirred overnight at room temperature. More carbodiimide (0.3 g, 2 mmol) was added and after stirring for one hour the reaction mixture was concentrated in vacuo onto silica gel (15 g). Purification by chromatography on silica gel (125 g) eluting with methanol:methylene chloride (3:97 to 1:19) and recrystallization from methanol:ethyl acetate gave, after drying under high vacuum, 4-amino-N-(2-hydroxyethyl)benzamide (1.65 g) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ: 3.26 (q, J=6 Hz, 2H, NCH2), 3.46 (q, J=6 Hz, 2H, OCH2), 4.68 (t, J=5.5, 1H, OH), 5.58 (br s, 2H, NH2), 6.51 (d, J=8.5 Hz, 2, Ar), 7.56 (d, J=8.5 Hz, 2H, Ar), 7.94 (br t, J=5.4 Hz, 1H, CONH). Mass spectrum (CI—CH4): 181 (M+1, 100%). Anal. Calculated for C912N2O2: C, 59.99; H, 6.71; N, 15.55. Found: C, 60.05; H, 6.72; N, 15.55.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=[C:10]([CH:18]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:19]([NH2:21])=[S:20])[CH:9]=1.[C:35](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:35][S:20][C:19](=[NH:21])[CH:18]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:13]2[O:14][CH2:15][CH2:16][O:17][C:12]=2[CH:11]=1)[NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:27][CH:28]=1
Reactant: O=C([O-])O
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCCO2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 750 mg of Me3O+BF4− to a solution of 1.92 g of 2-(8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 20 ml of acetonitrile, the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[CH2:4][C:5]#[N:6].[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH:21]=O)=[CH:16][N:15]=1.N>C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]1[C:5]([NH2:6])=[N:20][C:18]2[N:19]=[C:14]([NH2:13])[N:15]=[CH:16][C:17]=2[CH:21]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: C
Agent: N
Product: Cc1cc(C)c(-c2cc3cnc(N)nc3nc2N)c(C)c1

Procedure:
The title compound was prepared according to Example 1, starting from 0.915 g of 2,4,6-trimethyl-benzyl cyanide and 0.76 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 276-282° C.; CIMS (1% ammonia in methane): m/z (relative intensity) 279 (MH+, 54), 280 (MH+ +1, 100)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:11][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9]1.[Br:31][C:32]1[N:37]=[C:36]([C:38]([OH:40])=O)[C:35]([F:41])=[CH:34][CH:33]=1>>[Br:31][C:32]1[N:37]=[C:36]([C:38]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([CH2:14][OH:15])[CH2:11][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:9]2)=[O:40])[C:35]([F:41])=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(c2ccncc2N)C1
Reactant: O=C(O)c1nc(Br)ccc1F
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](CO)CN(c2ccncc2NC(=O)c2nc(Br)ccc2F)C1

Procedure:
Following Method 11 of Example 305, cis (+/−)-tert-butyl 1-(3-aminopyridin-4-yl)-5-((tert-butyldimethylsilyloxy)methyl)piperidin-3-ylcarbamate and 6-bromo-3-fluoropicolinic acid were coupled. Following purification by RP HPLC the product fractions were allowed to stand at it overnight in the 0.1% TFA acetonitile/water solution which removed the silyl group. Upon subsequent lyophilization, cis (+/−)-tert-butyl 1-(3-(6-bromo-3-fluoropicolinamido)pyridin-4-yl)-5-(hydroxymethyl)piperidin-3-ylcarbamate was obtained and used in Suzuki reactions directly. LCMS (m/z): 524.0/526.0 (MH+); LC Rt=2.90 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6](=[NH:14])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:19][CH:20]=O.C(=O)(O)[O-].[Na+]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]=[CH:20][N:14]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(C(=N)Nc2ccccc2)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cccc(-c2nccn2-c2ccccc2)c1
Yield: 75.5 %

Procedure:
To a 500 mL round bottom flask was added 3-methoxy-N-phenylbenzimidamide (7.81 g, 34.5 mmol), 2-chloroacetaldehyde solution (50%, 9.4 mL, 69 mmol), sodium bicarbonate (5.80 g, 69 mmol), and 150 mL 2-propanol. The reaction mixture was heated at reflux for 3 h under nitrogen. The solvent was removed under vacuum and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with water, brine, dried over magnesium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with 50% and 100% ethyl acetate/hexane to give pure product (6.52 g, 75%).
Reaction SMILES: [NH2:1][C:2]([C@H:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]>>[NH2:1][C:2]([C@H:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[CH:11][CH:10]=2)[N:5]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:3]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(N)=O)CC[C@H]1c1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1[C@@H](C(N)=O)CC[C@H]1c1ccc(OCc2ccccc2F)cc1

Procedure:
The title compound was synthesized (145 mg, 79%) following a similar procedure as set out earlier in Description 10 starting from 1,1-dimethylethyl (2R,5S)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidine carboxylate (D23, 130 mg, 0.44 mmol) and 1-(bromomethyl)-2-fluorobenzene (166 mg, 0.88 mmol); Rt (HPLC) 5.55; MS: (ES/+) 437 m/z: [M+Na+], C23H27FN2O4 requires 414; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.48-7.63 (m, 3H); 4.30-4.45 (m, 2H); 4.18-4.29 (m, 2H); 6.90-7.06 (m, 3H); 5.10 (s, 2H); 4.56-4.82 (m, 1H); 4.10-4.18 (m, 1H); 2.12-2.26 (m, 1H); 1.98-2.12 (m, 1H); 1.60-1.95 (m, 2H); 0.98-1.42 (m, 9H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:20]=[C:19]([CH2:21][OH:22])[C:18]=2[CH:23]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]2[CH:20]=[C:19]([CH2:21][O:22][S:8]([CH3:7])(=[O:10])=[O:9])[C:18]=2[CH:23]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)C(CO)=C2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)C(COS(C)(=O)=O)=C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.1 ml (76 mmol) of pyridine and 3.6 ml (46 mmol) of methanesulphonic acid chloride are added at 0° C., while stirring, with the exclusion of moisture, to 5.0 g (30.5 mmol) of (5-methoxybenzocyclobuten-1-yl)-methanol in 50 ml of dichloromethane. The mixture is then stirred at room temperature for a further 18 hours to complete the reaction 50 ml of ice-water are then added and the whole is stirred for 30 minutes. The organic phase is separated off, washed once in each case with 2N sodium hydroxide solution, 2N hydrochloric acid and water, dried over sodium sulphate and concentrated under reduced pressure. Methanesulphonic acid (5-methoxybenzocyclobuten-1-ylmethyl) ester is obtained in the form of a viscous oil, Rf=0.4, toluene/ethyl acetate (9:1).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH:26]=[CH:25][CH2:24]3)[C:9]=2[CH:8]=1)=S)[CH:2]=[CH2:3].C(O)(=[O:31])C>>[CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH:26]=[CH:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:31])[CH:2]=[CH2:3]
Reactant: CC(=O)O
Reactant: C=CCNC(=S)c1ccc2c(c1)N(C(C)CN1CC=CC1)c1ccccc1S2
Product: C=CCNC(=O)c1ccc2c(c1)N(C(C)CN1CC=CC1)c1ccccc1S2

Procedure:
The procedure is as described in Example 17, but starting with N-allyl-10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (1.49 g), in acetic acid (25 cc) and a solution of mercuric acetate (1.16 g) in acetic acid (25 cc). The yellow meringue-like residue (1.27 g) is purified by chromatography on a column (height: 23 cm; diameter: 2.6 cm) of silica gel (0.04-0.63 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with ethyl acetate (1.5 liters) and collecting 25-cc fractions. Fractions 10 to 58 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-allyl-10-[1-(2,5-dihydro-1-pyrrolyl)-2-propyl]-2-phenothiazine-carboxamide, L series (0.45 g), in the form of a yellow resin.