Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[C:5]([CH:15](O)[CH:16]([CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[C:17](OC)=[O:18])=[CH:4][CH:3]=1.[ClH:35]>CO.O>[ClH:35].[F:1][C:2]1[N:7]=[C:6]2[C:5]([CH:15]=[C:16]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:17](=[O:18])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1ccc(F)nc1NC(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c2nc(F)ccc2cc1C1CCNCC1

Procedure:
The mixture of tert-butyl 4-(1-(6-fluoro-2-pivalamidopyridin-3-yl)-1-hydroxy-3-methoxy-3-oxopropan-2-yl)piperidine-1-carboxylate (238 mg, 0.494 mmol), and concentrated HCl(1 mL) in MeOH (1 mL) and H2O (1 mL) was refluxed under N2 over night. The solvents were removed on rotary vacuum, the residue, as a yellow solid, was triturated with cold EtOH (2×3 mL), filtrated and dried under vacuum to afford an expected product, a yellow solid(139 mg, 99% yield); 1H NMR (400 MHz, MeOD) δ ppm 1.27 (s, 1H), 1.83-1.95 (m, 2H), 2.13 (d, J=14.10 Hz, 2H) ,3.06-3.18 (m, 3H), 3.49 (d, J=12.84 Hz, 2H), 6.47 (d, J=8.81 Hz, 1H), 7.69 (s, 1H),7.85 (d, J=9.06 Hz, 1H); Mass spec. 248.13 (MH+), Calc. for C13H14FN3O 247.11.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][CH2:22][CH2:21][C:20]=3[CH:24]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:23]1[C:19]2[CH:18]=[CH:17][C:16]([C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])=[CH:24][C:20]=2[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc2c(c1)CCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
To a solution of 4-(2,3-dihydro-benzofuran-5-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.50 g, 1.5 mmol) in 10 mL of DCM, was added 1 mL of TFA. The reaction mixture was stirred at ambient temperature for 2.5 hours, then solvent was removed by reduced pressure to yield the title product (0.3 g, 1.2 mmol, 77% yield). MS (ESI) m/z 232.3 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.14 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].Br[CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:12][O:11][CH:10]([O:13][CH3:14])[CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7]
Reactant: COC(CBr)OC
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cn1ccnc1C=O)OC
Temperature: 110 °C
Yield: 31.6 %

Procedure:
To a solution of the imidazole-2-carboxaldeyde (0.41 g, 4.27 mmol) in DMF (1 mL) was added 1.1 eq. of 2-bromo-1,1-dimethoxyethane (0.79 g, 4.69 mmol), potassium carbonate and a catalytic amount of potassium iodide. The reactions were heated at 110° C. for 18 hrs followed by evaporation to dryness and purified utilizing a Biotage SP4 with a gradient method of 5-50% methanol in DCM to yield the desired compound (248 mg, 1.35 mmol, 32% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.9 (s, H), 7.85 (s, H), 7.55 (s, H), 5.82 (m, H), 4.75 (d, 2H), 3.45 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](I)[CH3:22]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][O:13][CH3:14])[CH:11]=1)[C:6]([O:8][CH2:21][CH3:22])=[O:7])#[N:2]
Reactant: COCc1cc(C#N)cc(C(=O)O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C#N)cc(COC)c1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
To a solution of 3-cyano-5-methoxymethyl-benzoic acid (90 mg, 0.469 mmol) in acetonitrile (3 mL) was added cesium carbonate (199 mg, 0.1 mmol) and ethyl iodide (44 μL, 0.563 mmol), respectively. The reaction mixture was stirred at reflux for 4 h. Upon cooling to room temperature, the reaction mixture was filtered and the filtrated was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo to afford ethyl 3-cyano-5-methoxymethyl-benzoate (88 mg, 70%).
Reaction SMILES: CS(O[CH2:6][CH:7]1[N:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([F:24])[C:22]=3[CH:23]=[C:15]2[C:14]2[N:13]=[C:12]([Cl:25])[CH:11]=[CH:10][C:9]=2[CH2:8]1)(=O)=O.[C-:26]#[N:27].[K+]>CN(C=O)C.O>[Cl:25][C:12]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:6][C:26]#[N:27])[N:16]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([F:24])[C:22]=4[CH:23]=[C:15]3[C:14]=2[N:13]=1
Reactant: CS(=O)(=O)OCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Temperature: 80 °C
Reaction time: 15 h
Yield: 76.4 %

Procedure:
A mixture of (2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)methyl methanesulfonate (1 g, 2.52 mmol) and KCN (491 mg, 7.55 mmol) in DMF (15 mL) was stirred at 80° C. for 15 hours. The mixture was diluted with water (30 mL) and extracted with EA (20 mL×3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated. The residue was purified by column (PE:EA=1:1) to afford the desired product of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetonitrile (600 mg, yield: 73%). 1H-NMR (CDCl3, 400 MHz) δ 7.49 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.18 (d, J=8.0 Hz 2H), 7.09 (d, J=8.4 Hz, 1H), 6.77˜6.79 (m, 1H), 5.00˜5.06 (m, 1H), 3.48˜3.54 (m, 1H), 3.27 (d, J=16.4 Hz, 1H), 2.54˜2.59 (m, 1H), 2.37˜2.44 (m, 1H). MS (M+H)+: 312/314.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[C:21]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:11][C:12]2[C:21]([C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(=O)c1cccc(C(=O)OC)c1O
Product: CCC(=O)c1cccc(C(=O)OC)c1OC(=O)c1ccc(C)cc1
Reaction time: 4 h

Procedure:
This compound was prepared in three steps according to the methods described for Intermediate XC (first step) and Intermediate LXXX (second and third steps). In the first step, 4-methylbenzoyl chloride was used instead of 2-furanecarbonyl chloride and methyl 2-hydroxy-3-propionylbenzoate was used instead of ethyl 2-hydroxy-3-propionylbenzoate. The reaction lasted 4 hours at room temperature, yielding methyl 2-(4-methylbenzoyloxy)3-propionylbenzoate. This compound was used without purification by column chromatography for the second step, that lasted 1.5 hours at 100° C. In the third step, 96% sulfuric acid was used instead of 37% hydrochloric acid. The title compound melted at 174°-175° C. after crystallization from ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[N:14]=[C:13]([CH2:15]O)[CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:19])=O.C(=O)([O-])O.[Na+]>O>[Cl:19][CH2:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[N:14]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ccnc(Cl)c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: ClCc1cccc(Oc2ccnc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 6-[(2-chloro-4-pyridyl)oxy]-2-pyridine-methanol (10.2 g, 0.043 mol) and thionyl chloride (10 mL) is stirred at room temperature for 90 minutes. Excess thionyl chloride is hydrolyzed by adding water to the reaction mixture until no further reaction is observed. The reaction mixture is then neutralized with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product (10.6 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:15]I>>[CH3:15][N:4]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: CI
Reactant: Nc1n[nH]c(-c2ccccn2)n1
Agent: [H-]
Agent: [Na+]
Product: Cn1nc(N)nc1-c1ccccn1

Procedure:
The 1-alkyl-3-amino-5-pyridinyl-1,2,4-triazole may be readily prepared from the corresponding 3-amino-5-pyridinyl-1,2,4-triazole under alkylating conditions. For instance, reaction of 3-amino-5-pyridinyl-1,2,4-triazole with sodium hydride followed by addition of methyl iodide yields the 1-methyl-3-amino-5-pyridinyl-1,2,4-triazole plus other isomers. Separation of the desired product may be readily accomplished by chromatography, distillation and the like.
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>CCO>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:6]2[CH2:7][CH2:8][C:3]([CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:5]2)=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCOC(=O)C1(C)CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(C)CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a solution of ii (0.9 g, 4.35 mmol) in EtOH (10 mL) was added DIPEA (2.30 mL, 13 mmol) at RT and the mixture stirred at RT for 10 min followed by addition of 5-bromo-2-chloropyrimidine (0.7 g, 3.6 mmol). The mixture was heated at 70° C. for 1 h. The solvent was evaporated and the crude residue purified by chromatography on silica eluting with 1.5% EtOAc:hexane to obtain iii (0.90 g, 75%). 1H NMR (DMSO-d6, 400 MHz): δ 1.17 (s, 3H), 1.21 (t, J=7.20 Hz, 3H) 1.40 (m, 2H), 2.00 (m, 2H), 3.24 (m, 2H), 4.11 (m, 2H), 4.15 (q, J=7.20 Hz, 2H), 8.43 (s, 2H). MS: 328.08 [M+H]+.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH2:14]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:28]1([P:34](Cl)(Cl)=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCCCCC.C1CCCCC1>[C:28]1([P:34]2(=[O:35])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: O=P1(c2ccccc2)c2ccccc2CN1c1ccccc1
Temperature: 26 °C
Reaction time: 2 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (3.90 g, 0.061 mol) in hexane was added to a solution of tetramethylethylenediamine (1.8 g, 0.0155 mol) in 30 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-benzylaniline (5.5 g, 0.03 mol) in 30 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 2 hours at 26° C. and then cooled to 0° C. A solution of phenylphosphonic dichloride (6.25 g, 0.032 mol) in 30 ml. of anhydrous cyclohexane was added dropwise to the suspension over a period of 15 minutes and the resulting mixture was stirred for 0.5 hours at 0° C., then for 2.5 hours at 26° C. The reaction was quenched with the rapid addition of 6 ml. of acetic acid. The reaction mixture was concentrated in vacuo and the residue partitioned in methylene chloride and water. The layers were separated and the methylene chloride layer was washed with 5% hydrochloric acid, sodium bicarbonate, then water. The methylene chloride layer was dried over magnesium sulfate, concentrated in vacuo and the resulting residue was slurried in anhydrous diethyl ether and allowed to stand at 0° C. for 40 hours. The slurry was filtered and the resulting yellow precipitate was dissolved in a minimal amount of hot ethyl alcohol. The ethyl alcohol solution was diluted with petroleum ether to yield 1,2-diphenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as white fluffy crystals. A second crop was obtained and the combined product yield was recrystallized from ethanol to yield 1,2-diphenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (3.0 g, 33% yield) as fluffy needles having a melting point of 227°-229° C. and the following analysis:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[CH2:28][CH2:27][CH:26]([C:29](O)=[O:30])[C:25]3=[O:32])=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:29]([CH:26]1[CH2:27][CH2:28][N:24]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH2:17]3)[C:25]1=[O:32])=[O:30]
Reactant: O=C(O)C1CCN(c2ccc3c(c2)CCC3)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc3c(c2)CCC3)C1=O
Yield: 43 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxylic acid (0.111 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.077 g (43%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2,3-dihydro-1H-inden-5-yl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])=[C:28]([CH3:37])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[CH:6]=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:36])[N:33]([CH3:34])[CH3:35])=[C:28]([CH3:37])[N:27]=2)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1
Reactant: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C(N)=O)ccc1C(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C(N)=O)ccc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl {(1S,2R)-2-[(6-carbamoyl-5-{[5-(dimethylcarbamoyl)-6-methylpyridin-2-yl]amino}pyridin-3-yl)amino]cyclohexyl}carbamate (48 mg, 0.094 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.10 mL, 1.3 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[5-(dimethylcarbamoyl)-6-methylpyridin-2-yl]amino}pyridine-2-carboxamide. MS ESI calc'd. for C21H30N7O2 [M+H]+ 412. found 412. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.55 (d, J=2.3 Hz, 1H), 7.91 (s, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.45 (d, J=. 8.4 Hz, 1H), 7.33 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.62 (d, J=7.0 Hz, 1), 3.63-3.50 (m, 1H), 3.37-3.27 (m, 1H), 2.99 (s, 3H), 2.82 (s, 3H), 2.34 (s, 3H), 1.88-1.72 (m, 2H), 1.69-1.50 (m, 4H), 1.48-1.31 (m, 2H).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:31]1[C:32]2[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.N12CCCN=C1CCCCC2>CC(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:31]4[C:32]5[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:28][CH2:29]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: Fc1ccc(-c2cn(CCN3CCCC3)c(C3CCNCC3)n2)cc1Cl
Reactant: CC1(C)C(=O)Nc2ncnc(Cl)c21
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(Cl)c5)cn4CCN4CCCC4)CC3)c21
Yield: 13.5 %

Procedure:
Combine 4-[4-(3-Chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidine tris hydrochloride (0.3 g; 0.00062 mol), 4-chloro-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.16 g; 0.0008 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.76 mL; 0.0051 mol) into IPA (10 mL) and stir at 120° C. for 16 h; cool and concentrate. Quench the reaction with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA layer and purify by column chromatography using 0-5% MeOH/DCM as eluent to afford the title compound (0.045 g; 13.5%). MS (ES+): m/z=538 (M+1).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[C:8]1[C:9]([C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1>Cl>[CH2:1]([O:6][C:8]1[C:9]([C:14]2([OH:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[N:10][CH:11]=[CH:12][N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCO
Reactant: OC1(c2nccnc2Cl)CN2CCC1CC2
Agent: Cl
Product: CCCCCOc1nccnc1C1(O)CN2CCC1CC2
Temperature: 70 °C

Procedure:
To a solution of 30 ml of pentanol that had reacted with 0.5 g of Na (0.022 mol) was added 1.7 g of (7) (0.0071 mol). The reaction was heated to 70° C. for 2 h, the reaction cooled to ambient temperature, and 30 ml of 1 N HCl was added. The excess pentanol was azeotroped off with water and the residue made basic with 5 N NaOH. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, dried, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol-0.5% N and then with 10% ethanol-1% NH4OH-CHCl3 to give 1.68 g of 3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octan-3-ol. NMR ppm (CDCl3) 0.97 (3H, t), 1.2 (1H, m), 1.45 (6H, m), 1.87 (2H, m), 2.3 (1H, m), 2.4 (1H, t), 2.8 (1H, m), 2.93 (3H, m), 3.1 (1H, m), 3.98 (1H, s), 4.28 (1H, d), 4.42 (2H, m), 8.01 (1H, d), 8.11 (1H, d). A solution of 1.48 g of this alcohol (0.0051 mol) in 50 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 5 ml of CH2Cl2 was added dropwise. The cooling was removed, the reaction stirred 1.5 h and then heated to reflux for 45 min. After cooling to ambient temperature, ice-water was added to the reaction and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts washed with brine, and the solvent evaporated. The residue was purified by radial chromatography eluting with 5% ethanol- 0.5% N4OH-CHCl3 to give 1.27 g of 3-chloro-3-(3-pentyloxypyrazinyl)-1-azabicyclo[2.2.2]octane. NMR ppm (CDCl3) 0.99 (3H, t), 1.35-1.8 (7H, m), 1.9 (2H, m) 2.37 (1H, m), 2.6-2.82 (2H, m), 3.0 (1H, t), 3.15 (2H, m), 3.6-4.1 (2H, m), 4.42 (2H, t), 8.06 (2H, m). A mixture of 1.05 g of this chloride (0.0034 mol) and 0.4 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated 1 h at 60 psi of H2. The catalyst was filtered off, 25 ml of isopropanolic HCl was added, and the solvent was evaporated. The residue was recrystallized from ethyl acetate to give 0.28 g of (25), mp 166°-167° C. NMR ppm (CDCl3) 0.95 (3H, t), 1.41 (4H, m), 1.57-1.9 (5H, m), 2.13 (2H, m), 2.45 (1H, m), 3.12 (1H, m), 3.3-4.46 (3H, m), 3.55 (1H, m), 3.7 (1H, m), 4.3 (1H, q), 4.37 (2H, t), 8.03 (1H, d), 8.1 (1H, d). Anal. C16H25N3O-HCl requires C: 61.62; H: 8.40; N: 13.47%. Found C: 61.39; H: 8.07; N: 13.48%.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>C1COCC1>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)=[O:29])[S:14][N:13]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Solvent: C1CCOC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a suspension of [4-Carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester (125 mg, 0.298 mmol) in THF (1 mL) was added 1-(3-aminopropyl)-4-methylpiperazine (70 mg, 0.45 mmol). The mixture was shaken at 50° C. overnight, cooled to ambient temperature, and loaded directly onto a radial chromatograph followed by elution with chloroform/methanol/concentrated ammonium hydroxide (50/5/1) to afford a white solid (121 mg, 0.251 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ1.72 (t, J=5.81 Hz, 2H), 2.20-2.85 (m, 10H), 2.28 (s, 3H superimposed on multiplet from 2.20-2.85), 2.35 (s, 3H superimposed on multiplet from 2.20-2.85), 3.39 (t, J=5.4 Hz, 2H), 5.51 (s, 2H), 5.74 (broad s, 1H), 6.74 (d, J=8.3 Hz, 2H), 7.05 (s, 1H), 7.58 (broad s, 1H), 11.01 (broad s, 1H) ppm; MS (APCI, m/z): 483 [M+H]+.
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)(C(C)(C)C)(C)C.CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[OH:20][C:21]1[CH:22]=[C:23]([F:28])[C:24]([CH:5]=[O:6])=[C:25]([F:27])[CH:26]=1
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(F)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(O)cc1F
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 53 mL, 69.3 mmol) was added slowly at −78° C. to a solution of intermediate 19, 1-(tert-butyldimethylsilyl)oxy-3,5-difluorobenzene (15.3 g, 62.6 mmol) and TMEDA (10.5 mL, 69.3 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (5.33 mL, 69.3 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and then the reaction mixture was stirred at RT for 12 h. The aqueous layer was extracted with EtOAc (200 mL). The organic layer was separated. The organic layer was washed with sat. NaHCO3, then H2O was added, HCl was added to attain pH˜3-4, the organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (9.7 g, 97%, 61.3 mmol) as a white solid. 1H NMR data (dmso-d6): 11.54 (br.s, 1H, OH), 10.00 (s, 1H, CHO), 6.50-6.57 (m, 2H, H—Ar).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8](Cl)=[N:7][C:6]=2[CH:16]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C1(C)C=CC=CC=1>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3=[CH:12][S:13][CH:14]=[C:9]3[C:8]([N:23]3[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]3)=[N:7][C:6]=2[CH:16]=1
Reactant: Cc1ccc2c(c1)N=C(Cl)c1cscc1O2
Reactant: OCCN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N=C(N1CCN(CCO)CC1)c1cscc1O2

Procedure:
7-Methyl-10-chloro-thieno[3,4-b][1,5]benzoxazepine (Example 7) is reacted with 20 ml. of N-(2-hydroxyethyl)-piperazine in 20 ml. of dry toluene as described in Example 1, giving the base compound which is further reacted with fumaric acid, giving the desired product as the fumarate salt, m.p. 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(C)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(C)(F)F)c(Cl)c1
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (696 mg, colorless oil) from 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanone (610 mg, 2.45 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (446 mg, 3.68 mmol) in a similar manner to Step-4 of Amine-1.