Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH2:4][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(CCl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc([N+](=O)[O-])cc1Cl
Yield: 44.4 %

Procedure:
Using 0.21 g of 2-chloro-4-nitrobenzyl chloride, 3 ml of N,N-di-methylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.15 g of 2-(2-chloro-4-nitrobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (38)).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]=O>>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: Cc1cn(CCN)c(C)n1
Reactant: Cc1cccc(CCC=O)c1C
Product: Cc1cccc(CCC2NCCn3c(C)nc(C)c32)c1C

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,3-dimethyl-phenyl)-propionaldehyde. LC-MS: tR=0.61 min.; [M+H]+=284 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([Cl:14])[CH:10]=[C:9]([Cl:15])[C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]2[C:9]([Cl:15])=[CH:10][C:11]([Cl:14])=[C:12]([Cl:13])[C:2]=2[Cl:1])[CH2:26][CH2:25]1
Reactant: Clc1cc(Cl)c(OCC2CO2)c(Cl)c1Cl
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2c(Cl)cc(Cl)c(Cl)c2Cl)CC1
Yield: 44.3 %

Procedure:
To a solution of 2-((2,3,4,6-tetrachlorophenoxy)methyl)oxirane (45 mg, 0.16 mmol) in ethanol (0.50 mL) was added 4-(2-methoxyphenyl)piperazine (33 μL, 0.19 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1007 (34 mg, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([N:24]([CH2:28][CH2:29]C)[CH2:25][CH2:26]O)=[O:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:31]C(C)([O-])C.[K+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:29][CH2:28][N:24]([CH:25]([CH3:26])[CH3:31])[C:22]4=[O:23])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(CCO)C(=O)Nc1ccc(N2CCN(c3ccc(OC)cc3)CC2)cc1
Reactant: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(N4CCN(C(C)C)C4=O)cc3)CC2)cc1
Yield: 76.8 %

Procedure:
To a slurry of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-N′-2-methylethyl-N′-[2-hydroxyethyl]urea (Formula Va, 35.0 mmol, 14.4 g) in tetrahydrofuran (600 mL) was added potassium tert-butoxide (123.0 mmol, 11.2 g). The reaction vessel was cooled in an ice bath and a tetrahydrofuran (200 mL) solution of p-toluenesulfonyl chloride (57.0 mmol, 10.9 g) was added over a period of 0.5 hours. The resulting beige mixture was allowed to stir at ambient temperature for 14 hours before addition of water (200 mL). The mixture was filtered and the product was washed with water (200 mL) and dried. A white powder of 1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-oxoimidazolidine (10.6 g) was obtained in 77% overall yield from 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J=9.2 Hz, 2 H, Ar), 6.96 (d, J=9.2 Hz, 2 H, Ar), 6.95 (d, J=9.2 Hz, 2 H, Ar), 6.86 (d, J=9.2 Hz, 2 H, Ar), 4.30-4.20 (m, 1 H, CH), 3.76 (s, 3 H, OCH3), 3.82-3.72 (m, 2 H, CH2), 3.45-3.38 (m, 2 H, CH2), 3.32-3.20 (m, 8 H, CH2). The product was shown by HPLC retention time and NMR spectroscopy to be identical to an authentic standard prepared by the literature procedure. More importantly, the product of the present invention was demonstrated by HPLC to be purer (99.97 area %) relative to that of material prepared by the literature procedure (99.39 area %). Furthermore the product of the present invention did not contain the impurity which may negatively impact the quality of Pramiconazole, and which was present in material prepared by the literature procedure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]2[C:7](O[C:10](=O)[C:3]=2[CH:2]=1)=O.N[C:13]1C=CC=CC=1>>[NH:1]1[C:2]2[C:4](=[CH:7][CH:13]=[CH:10][CH:3]=2)[CH:5]=[CH:6]1
Reactant: O=C1OC(=O)c2cnccc21
Reactant: Nc1ccccc1
Product: c1ccc2[nH]ccc2c1

Procedure:
In like fashion, reaction of 3,4-pyridinedicarboxylic anhydride (Formula Vb hereinbelow) with an aniline of Formula VI or an indole of Formula VII (Z-H hereinbelow) produces a mixture of 3-(Z-CO)-4-pyridinecarboxylic acid (Formula IIc) and 4-(Z-CO)-3-pyridinecarboxylic acid (Formula IId). The mixture is in turn reacted with a diarylamine of Formula III to produce an isomeric mixture of furo[3,4-c]pyridine-1(3H)-one (Formula Ic) and furo-[3,4-c]pyridine-3(1H)-one (Formula Id). ##STR22##
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:13][CH:14]=O>C(O)C.O.N>[N:1]1[CH:13]=[CH:14][N:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=12
Reactant: COC(=O)c1cccnc1N
Reactant: O=CCCl
Agent: N
Solvent: O
Solvent: CCO
Product: COC(=O)c1cccn2ccnc12

Procedure:
A mixture of methyl 2-aminonicotinate (WO 89/01488 pg33, prep 17) (1 g, 6.56 mmol), and chloroacetaldehyde (1.05 mL, 6.56 mmol) in ethanol (5 mL) was heated under reflux for 18 hours. The cooled mixture was diluted with water (10 mL), 0.88 ammonia (1 mL) added and the solution concentrated in vacuo. The residue was dissolved in methanol and the dark solution treated with charcoal, the mixture filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (97:2.5:0.5) as eluant, and the product triturated with ether, to afford the title compound, 768 mg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:8]([NH2:21])[N:7]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:22][C:11]1[N:12]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[C:13]2[C:9]([N:10]=1)=[C:8]([NH2:21])[N:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:14]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClC(Cl)Cl
Product: COCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
2-{[2-(Methoxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.61 g) was dissolved in chloroform (20 mL) and cooled to 0° C. To this solution was then added N-bromosuccinimide (1.02 g) gradually, keeping the temperature at ˜2° C. The reaction was stirred at 2° C. for around 15 minutes before being allowed to warm to room temperature. The reaction mixture was then stirred under nitrogen for 5 hours. The reaction mixture was quenched with water (100 mL) and stirred rapidly before the organic layer was separated using a hydrophobic frit. The organic was evaporated under reduced pressure to give a dark brown gum. This material was purified by silica chromatography (ISCO) eluting initially with 0-70% ethyl acetate: cyclohexane holding isocratic at 70% ethyl acetate; cyclohexane until a minor impurity was eluted. The gradient was then resumed from 70%-95% ethyl acetate: cyclohexane. This gave the title compound as a white solid (1.4489 g)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=[C:6]([C:8](O)=[O:9])[CH:7]=1.O1CCCC1.[OH-].[Al+3].[Li+].[OH-].[OH-].[OH-]>O>[Cl:1][C:2]1[C:3]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)[CH:24]=[CH:25][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1
Reactant: O=C(O)c1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Agent: [Al+3]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)nc2)c(Cl)c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
0.49 g of 3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-carboxylic acid (71) (1.12 mmol) prepared in Example 58 was added to 5 mL of tetrahydrofuran, and cooled to −80° C. 0.09 g of lithium aluminum hydroxide (2.24 mmol) was slowly added thereto. After stirring for 2 hours, the temperature of the reactant was slowly raised to room temperature, and further reacted 2 hours. A small amount of water was added thereto terminate the reaction, and concentrated under reduced pressure. Then, the resultant was dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=20/1) to obtain 0.44 g of yellow crystal, [3-chloro-6′-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-[2,3′]bipyridinyl-5-yl]-methanol compound (yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[C:31]5[O:30][CH2:29][CH2:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C.Cl>>[NH2:38][CH2:39][CH2:40][NH:41][C:12](=[O:14])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[C:31]4[O:30][CH2:29][CH2:28][C:27]=4[CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2,3-dihydro-benzofuran-7-yl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl and neutralisation, the title compound.
Reaction SMILES: C([O-])(O)=O.[Na+].O.[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([C:22]([SH:25])([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CCO>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([C:22]([CH3:23])([S:25][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])[CH3:24])[C:19]([OH:21])=[O:20])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(Sc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
NaHCO3 (14.5 g, 172 mmol, Eq: 2.5) and H2O (210 mL) were added to a slurry of (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (19.5 g, 68.8 mmol, Eq: 1.00) in EtOH (70.0 mL). After 20 min. the mixture became homogeneous, 1-fluoro-2-nitrobenzene (9.71 g, 7.00 mL, 68.8 mmol, Eq: 1.00) was added and the mixture heated to reflux for 6 h. The mixture was cooled to RT, poured into H2O (300 mL) and extracted with MTBE. The aqueous layer was acidified to pH 5 with 1 N HCl and extracted with Et2O. The combined organic extracts were dried over Na2SO4 filtered and concentrated to give (R)-2-(benzyloxycarbonylamino)-3-methyl-3-(2-nitrophenylthio)butanoic acid (18.7 g, 67.2%) as a light yellow oil which was used without purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:29][CH2:28]2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[CH:27]2[CH2:28][CH2:29]2)[O:23][CH2:22][C:21]2[N:16]3[C@H:17]([CH3:31])[C:18](=[O:30])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C4CC4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C(=O)NN=C2COc3cc(C4CC4)c(NC4CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 3-(7-cyclopropyl-4(R)-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (Enantiomer 1, SFC (Table 1, Method 12) Rt=6.01 min., 0.300 g, 0.702 mmol) in DCM (9 mL) was added TFA (1.5 mL) and the reaction mixture was stirred for 2 h at ambient temperature. The solution was concentrated in vacuo to give 6-(azetidin-3-ylamino)-7-cyclopropyl-4(R)-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #64-1, Enantiomer 1, SFC (Table 1, Method 1) Rt=4.205 min., 0.291 g, 0.661 mmol, 94%). LC/MS (Table 1, Method 4) Rt=1.333 min.; MS m/z: 328 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CC([O-])(C)C.[K+].[N:18](OC(C)(C)C)=[O:19]>C1COCC1>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[N:18][OH:19])[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)CCCC2
Reactant: CC(C)(C)ON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ON=C1CCCc2cnc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
2-Chloro-5,6,7,8-tetrahydro-quinazoline (Eur. J. Med. Chem. 1982, 17, 75)(1.0 g; 5.9 mmol) is dissolved in THF (80 ml) and cooled to −78° C. KOtBu (667 mg; 5.9 mmol) in THF (10 ml) is added dropwise and stirred for 5 minutes after complete addition. t-Butyl nitrite (2 ml; 27.8 mmol) is added to the orange solution and the reaction mixture warmed to room temperature. After 10 minutes the reaction mixture is poured on water/HOAc (800/1 ml) and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to deliver the title compound as yellow-orange crystals (1.1 g; 95%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([SH:11])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[OH-].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>O>[NH2:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([S:11][CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: CCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCSc1cc(C(=O)O)cc(N)c1Oc1ccccc1
Reaction time: 16 h

Procedure:
5-Amino-3-mercapto-4-phenoxybenzoic acid (5.22 g) is suspended in water (150 ml), 1 N sodium hydroxide is added until pH 8, and n-butyl iodide (7.4 g) is added to the resulting solution. The reaction mixture is stirred for 16 hours whereafter 5-amino-3-n-butylthio-4-phenxoybenzoic acid is precipitated by addition of 1 N hydrochloric acid until pH 2.5. After collection, recrystallization from aqueous ethanol, and drying in vacuo at 65°C, the compound is obtained with a melting point of 131°-132°C.
Reaction SMILES: [CH:1]1([CH:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1.C(=O)=O.CC(O)C>>[CH:1]1([C@@H:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC(O)C1CC1
Agent: O=C=O
Solvent: CC(C)O
Product: COc1cc([N+](=O)[O-])ccc1OC[C@H](O)C1CC1

Procedure:
Racemic 1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol (45.1 g, mmol) in 2/1 MeCN/1-PrOH (451 mL) was resolved by chiral chromatography resolution using a CHIRALPAK® AD-H (3×25 cm, 5 μm) column under the Chiral-SFC conditions. The chromatographic conditions employed an 85/15 mixture of CO2/i-PrOH as the mobile solvent with a flow rate of 130 mL/min at 35° C. with the BPR pressure maintained at 100 bar and detector wavelength at 234 nM. Each 0.7 mL injection required a run time of 7 min. The chiral purity of the R enantiomer was determined to be greater than 99.9% at 234 nm based on SFC/UV area % using analytical SFC conditions. Concentration of the resultant eluant under vacuum using a rotary evaporator yielded (R)-1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol as yellow oil. Subsequent dissolution in 150 ml EtOH and reconcentration yielded the title compound in the form of a yellow oil, which solidified to form a light yellow solid (20.9 g) upon drying under high vacuum overnight. M.P. 77° C. 1H NMR (400 MHz, CDCl3): δ ppm 0.30-0.37 (m, 1H), 0.42-0.50 (m, 1H), 0.55-0.69 (m, 2H), 0.97-1.08 (m, 1H), 2.40-2.70 (bs, 1H), 3.41 (ddd, J=8.3, 8.3, 2.7 Hz, 1H), 3.93 (s, 3H), 4.10 (dd, J=9.3, 8.0 Hz, 1H), 4.23 (dd, J=9.3, 2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.2 Hz, 1H), 7.89 (dd, J=8.8, 2.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ ppm 153.7, 149.2, 141.7, 117.6, 111.5, 106.7, 74.4, 73.5, 56.2, 13.4, 2.7, 2.0. HPLC: 6.26 min retention time, 98.7% API; ZORBAX® column SB C18 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 100% A:0% B to 0% A:100% B for 8 min (Solvent A: 10% MeOH−90% H2O=0.2% H3PO4; Solvent B: 90% MeOH−10% H2O+0.2% H3PO4) Detection at 220 nm. LC/MS: m/e=254.3 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)=[CH:16][C:15]=2[CH2:30][N:31]([CH2:32][CH3:33])[C:43]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(-c2ccc3ncccc3c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc4ncccc4c3)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-quinolin-6-yl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([CH2:22][CH2:23][CH2:24][NH:25][CH3:26])[C:9]2=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36]>CC(C)=O>[CH2:34]([N:25]([CH2:24][CH2:23][CH2:22][N:10]1[C:9](=[O:27])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:13][C:12]2[CH:14]=[CH:15][C:16]3[C:21]([C:11]1=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:26])[CH:35]=[CH2:36]
Reactant: CNCCCN1C(=O)C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)CCCN1C(=O)C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-1-[3-(methylamino)propyl]-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (1.79 g), potassium carbonate (2.18 g) and acetone (50 ml) is added allyl bromide (0.65 g) under ice cooling, and the mixture is stirred at room temperature overnight. The insoluble materials are filtered off and acetone is distilled off, and the oily residue is purified by silica gel column chromatography (eluent, chloroform: methanol=20:1) to give 1-[3-(N-allyl-N-methylamino)propyl]-3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[C:19]([CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)#[CH:20]>>[CH:21]1([C:19]#[C:20][C:2]2[CH:3]=[C:4]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(NCCC(O)c1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1CCCCCC1
Product: O=C(NCCC(O)c1cccc(C#CC2CCCCCC2)c1)C(F)(F)F

Procedure:
Sonogashira coupling of N-(3-(3-bromophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (43) with ethynylcycloheptane, followed by flash chromatography (5-40% EtOAc/hexanes gradient), gave N-(3-(3-(cycloheptylethynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as an amber oil. Yield (0.507 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.42 (br s, 1H), 7.34-7.36 (m, 1H), 7.19-7.33 (m, 3H), 4.81 (q, J=4.0 Hz, 1H), 3.48-3.68 (m, 1H), 3.32-3.42 (m, 1H), 2.74-2.82 (m, 1H), 2.48 (br s, 1H), 1.85-2.00 (m, 4H), 1.70-1.80 (m, 4H), 2.46-1.64 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1.[NH3:42]>CO>[NH2:42][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:23]2[C:24]([F:41])=[C:25]([NH:29][S:30]([C:33]3[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=3[F:40])(=[O:32])=[O:31])[CH:26]=[CH:27][CH:28]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Solvent: CO
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(N)n3)s2)CC1
Yield: 30 %

Procedure:
Following a procedure analogous to Example 51, Step B using N-(3-{5-(2-chloro-4-pyrimidinyl)-2-[4-(methylsulfonyl)-1-piperazinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (0.140 g, 0.217 mmol) and 7M ammonia in MeOH (25 mL) the title compound was obtained (0.041 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (br. s., 1H), 7.84 (d, J=5.3 Hz, 1H), 7.63-7.73 (m, 1H), 7.37-7.48 (m, 1H), 7.17-7.34 (m, 4H), 6.58 (br. s., 2H), 5.65 (d, J=5.2 Hz, 1H), 3.60 (br. s., 4H), 3.26 (br. s., 4H), 2.92 (s, 3H). m/z (ES+): 626 [M+H]+.