Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1[F:28])=[O:17]>C(Cl)Cl.C1CCCCC1>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[C:16]([C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])=[O:17]
Reactant: COc1c(C)c(C(=O)c2ccc(C(F)(F)F)cc2F)c(OC)c2ccccc12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COc1c(C)c(C(=O)c2ccc(C(F)(F)F)cc2F)c(O)c2ccccc12

Procedure:
(1,4-dimethoxy-3-methylnaphthalen-2-yl)(2-fluoro-4-(trifluoromethyl) phenyl)methanone LJ123 (23 mg, 0.060 mmol) was used as a starting material and treated according to general procedure 12.1. The resulting yellow oil was purified through flash chromatography (DCM:Cyclohexane 1:1). The product was obtained as a yellow solid. Rf(DCM:Cyclohexane 1:1)=0.55. Yield=15 mg (68%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[S:10][C:9]([O:11][CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[N:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.BrC1C=CC2N=C(OC3CCNCC3)SC=2C=1>>[Br:1][C:2]1[CH:3]=[C:4]2[S:10][C:9]([O:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc3ncc(Br)cc3s2)CC1
Agent: Brc1ccc2nc(OC3CCNCC3)sc2c1
Solvent: O=C(O)C(F)(F)F
Product: Brc1cnc2nc(OC3CCNCC3)sc2c1

Procedure:
Compound 21C was prepared from Compound 21B and TFA in a similar manner to the procedure described for Compound 1B in Example 1. LC/MS (m/z)=314 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[C:14]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=1)[CH2:8][OH:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To 10.0 g (42.7 mmol) of acid 1 in 20 mL of dry THF at 0° C. was added 42.7 mL (42.7 mmol) of LAH (1.0M in THF). The reaction mixture was warmed to 50° C. and stirred for 15 min. After cooling the reaction to RT, 20% aqueous HCl was added until the solution turned clear. The solution was extracted with EtOAc (2×50 mL), and the combined EtOAc extract was washed (water, then brine), dried (MgSO4), filtered and concentrated to give 8.8 g (40.0 mmol) of 17 (94% yield): The product was directly used in the next step. TLC (20% EtOAc-80% hexanes) Rf 0.4; 1H-NMR (CDCl3) δ1.33 (s, 18H, 6(CH3)), 4.68 (s, 2H, CH2) 7.22 (d, J=1 Hz, 2H, Ar-H), 7.38 (t, J=1 Hz, 1H, Ar-H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12](O)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.CS(Cl)(=O)=O.[CH2:21]([N:23](CC)CC)C.[C-]#N.[Na+]>C1COCC1.CN1CCCC1=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([C:21]#[N:23])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)C2)cc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#CC1CCN(c2ccc(N)cc2)C1

Procedure:
1-(4-Nitrophenyl)pyrrolidin-3-ol and methanesulfonyl chloride were allowed to undergo the reaction in THF in the presence of triethylamine. The resulting compound and sodium cyanide were allowed to undergo the reaction in 1-methyl-2-pyrrolidone under heating. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-(4-aminophenyl)pyrrolidine-3-carbonitrile. NMR2: 1.48 (9H, s), 3.12-3.19 (2 H, m), 6.46-6.50 (2 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH3:36][C:37]([CH3:39])=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][N:25]([CH:37]([CH3:39])[CH3:36])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@H]1F
Reactant: CC(C)=O
Product: CC(C)N1C[C@@H](F)[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-4-fluoro-1-(1-methylethyl)pyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 317) and acetone (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH2:11][CH2:12][OH:13])[N:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:16]I>C1COCC1>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH2:11][CH2:12][O:13][CH3:16])[N:9]=[CH:10][C:3]=12
Reactant: OCCn1ncc2c(Br)cncc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCn1ncc2c(Br)cncc21
Reaction time: 2 h

Procedure:
A solution of 675 mg of 2-(4-bromo-pyrazolo[3,4-c]pyridin-1-yl)-ethanol (Intermediate 2.2; 2.79 mmol, 1 eq.) in 33 mL THF was treated at rt with 183 mg sodium hydride (55-60% suspension; 4.18 mmol, 1.5 eq.) and stirred for 30 min upon which 0.194 mL methyl iodide (3.07 mmol, 1.1 eq.) were added and stirring was continued for 2 h. The reaction mixture was quenched with water, extracted with ethyl acetate, the combined organic layers were dried and concentrated in vacuo. Flash column chromatography provided 500 mg of the corresponding methyl ether target compound (1.95 mmol, 70% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1)[CH3:2].C([Li])CCC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1.CCCCCC>[CH2:1]([O:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCn1c(C(=O)OCC)nc2ccccc21
Temperature: -60 °C
Yield: 35.9 %

Procedure:
1-Ethoxymethylbenzimidazole (1.76 g) was dissolved in dry THF (40 ml) in a dry argon atmosphere, cooled to -60° C., and a solution of n-butyl lithium (1.58M) in hexane (9 ml) was added dropwise with stirring and allowed to react for 1 hr. After ethyl chloroformate (1.62 g) was added dropwise, the mixture was slowly returned to room temperature and allowed to react overnight. THF was distilled off, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4, and the solvent was distilled off. Purification of the residue by column chromatography on silica gel gave the title compound (0.89 g) as an oily product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([CH3:24])[CH2:22][Cl:23])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([CH3:24])[CH2:22][Cl:23])=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(CCl)Cc1ccc(C(C)(C)C)cc1
Agent: O=S(=O)(O)O
Product: CC(CCl)Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
440 parts by weight of nitrating acid, consisting of 200 parts by weight of concentrated nitric acid and 240 parts by weight of concentrated sulfuric acid, are added dropwise to 448 parts by weight of 3-(p-tert.-butyl-phenyl)-2-methyl-propyl chloride, whilst cooling with ice. After stirring has been continued for 3 hours at room temperature, the crude product is poured onto ice and extracted with diethyl ether, the extract is washed with water, with aqueous NaHCO3 solution and again with water and is dried over Na2SO4, the solvent is evaporated and the residue is distilled.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=S)[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:30].C(OO)(C)(C)C>CO.O>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@:21]2([CH3:28])[CH2:22][O:23][CH2:24][C:25]([NH2:30])=[N:26]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=S)N1
Reactant: N
Agent: CC(C)(C)OO
Solvent: O
Solvent: CO
Product: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(N)=N1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A suspension of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholine-3-thione [Building block H, step b)] (1.25 g, 3.09 mmol) in methanol (57 ml) was treated with a solution of ammonia in methanol (26.5 ml, 185 mmol) and a solution of tert-butyl-hydroperoxide (4.28 ml, 30.9 mmol). After stirring at room temperature for 40 hours, the reaction mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, evaporated, and dried at high vacuum at room temperature to yield the crude (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine as a light brown foam which was dissolved in dioxane (20 ml) and treated with hydrochloric acid (1 M, 3.09 ml). After 40 minutes at room temperature the reaction mixtures was diluted with a saturated solution of hydrogen-carbonate and water. The mixture was extracted three times with ethyl acetate, then the aqueous phase basified with a solution of sodium hydroxide (28%). After four extractions with dichloromethane, the organic layers were combined, dried over sodium sulfate and evaporated. The (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as an off-white waxy solid (445 mg, 64% of theory).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=3)=[O:22])[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2cccc(O)c2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cccc(O)c3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(3-hydroxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1>>[F:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[F:33])[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1ccc(OCCCBr)cc1F
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccc(F)c(F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.820 g of 4-(3-bromopropoxy)-1,2-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.65 (1:1 EtOAc-heptane); Rt=5.30.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:16]3[C@@H:12]([CH2:13][NH:14][CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:32]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33]1>>[C:26]1([C:8]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@H:16]3[C@@H:12]([CH2:13][N:14]([C:38](=[O:39])[CH2:37][C:34]4[CH:35]=[CH:36][S:32][CH:33]=4)[CH2:15]3)[C@@:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Product: COc1ccccc1[C@]1(O)CCC(c2ccccc2)(c2ccccc2)[C@H]2CN(C(=O)Cc3ccsc3)C[C@H]21
Yield: 55.2 %

Procedure:
By working in accordance with Use Example 4, starting from 0.8 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindol-4-ol hydrochloride and 0.34 g of 3-thienylacetic acid, 0.53 g of (3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(3-thienyl)acetyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt with decomposition at 106° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=C(C)[S:10][C:6]=2[C:5]([F:12])=[CH:4][C:3]=1[F:13].[ClH:14].O1CCOCC1>C(O)CO.[OH-].[Na+]>[ClH:14].[NH2:8][C:7]1[C:2]([F:1])=[C:3]([F:13])[CH:4]=[C:5]([F:12])[C:6]=1[SH:10]
Reactant: Cc1nc2c(F)c(F)cc(F)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: C1COCCO1
Product: Nc1c(F)c(F)cc(F)c1S
Temperature: 125 °C
Yield: 73 %

Procedure:
A solution of 4,5,7-trifluoro-2-methylbenzothiazole (25.0 g, 123 mmol) in ethylene glycol (310 mL, 0.4 M) and 30% aq. NaOH (310 mL, 0.4 M) was degassed using a nitrogen stream then heated to a gentle reflux (125° C.) for 3 h. The solution was cooled to 0° C. and acidified to pH 3-4 using conc. HCl (appox. 200 mL). The solution was extracted with ether (750 mL) and washed with water (200 mL). The organic layer was dried over Na2SO4, filtered and treated with 2,2-di-tert-butyl-4-methylphenol (0.135 g, 0.5 mol%). After concentrating to dryness, the crude product was dissolved in anhydrous methanol (200 mL) and treated with an HCl solution in 1,4-dioxane (37 mL, 4 N, 148 mmol). The resulting mixture was concentrated to dryness, triturated with isopropylether (100 mL) and filtered to give 2-amino-3,4,6-trifluorothiophenol hydrochloride (19.3 g, 73%) as a light brown solid that was used without further purification. mp. 121-124 C; Rf 0.43 (30% ethyl acetate in heptane); Anal. Calcd for C6H5ClF3NS: C, 33.42; H, 2.34; N, 6.50; S, 14.87. Found C, 33.45; H, 2.27; N, 6.48; S, 14.96.
Reaction SMILES: Cl[C:2]1C(NCCCCCCSC)=NC=NC=1CC.[Cl:19][C:20]1[C:21]([N:27]([C:38]([Cl:40])=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[N:22][CH:23]=[N:24][C:25]=1[CH3:26].CSCCCCCCCCC1N=C(N)C2C(=CC=CC=2)N=1>>[Cl:19][C:20]1[C:21]([N:27]([C:38]([Cl:40])=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][S:36][CH3:37])=[N:22][CH:23]=[N:24][C:25]=1[CH2:26][CH3:2]
Reactant: CSCCCCCCCCN(C(=O)Cl)c1ncnc(C)c1Cl
Reactant: CCc1ncnc(NCCCCCCSC)c1Cl
Agent: CSCCCCCCCCc1nc(N)c2ccccc2n1
Product: CCc1ncnc(N(CCCCCCCCSC)C(=O)Cl)c1Cl

Procedure:
In the same manner as mentioned above, 5-chloro-N-(6-methylthiohexyl)-6-ethyl-4-pyrimidineamine, 5-chloro-N-chlorocarbonyl-N-(8-methylthiooctyl)-6-methyl-4-pyrimidineamine and N-chlorocarbonyl-N-(8-methylthiooctyl-4-quinazolineamine were synthesized.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:38]4[CH2:39][C:36]([F:40])([F:35])[CH2:37]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (1.4428 g, 2.57 mmol) from Step A, 3,3-difluoroazetidine hydrochloride (0.997 g, 7.70 mmol), triethylamine (1.788 ml, 12.83 mmol) and THF (25 mL) were heated in a 63° C. oil bath overnight. The reaction crude was purified by flash chromatography (SiO2, Isolute Flash Si; 100 g prepacked cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a light yellow solid foam as the titled compound. LCMS calc.=574.03. found=575.09 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C.CCCCCC>[C:12]1([CH2:11][CH2:10][NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccccc1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1NCCc1ccccc1
Yield: 85 %

Procedure:
According to GWM, 0.011 mol (=1.25 ml) of o-anisidine and 0.011 mol (=1.25 ml) of styrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:5) as eluent, the product N-(2-phenylethyl)-(o-methoxy)aniline being obtained as a slightly pink liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O>[CH3:19][S:20]([OH:22])(=[O:1])=[O:21].[OH:1][CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12]
Reactant: CS(=O)(=O)Cl
Agent: Cc1ncc([N+](=O)[O-])n1CCO
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A suspension of 200 parts of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole in 600 parts of pyridine is cooled to 5° C. in an ice bath and 140 parts of methanesulfonyl chloride is added portionwise at 0°-5° C. over a period of 4 hours. The mixture is then stirred at about 0° C. for 1 hour before it is slowly diluted with 600 parts of water while maintaining the temperature at 0°-5° C. The solid which forms is separated by filtration, washed with water and dried to give 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole methylsulfonate. Tosylates of 1-(2-hydroxyethyl)imidazoles are prepared in a similar manner using p-toluenesulfonyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([C:29](=[O:31])[CH3:30])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:9]1)=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[OH:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][CH2:33][NH:32][C:24]2[N:23]=[C:22]([C:18]3[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=3)[CH2:15][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)[C:29](=[O:31])[CH3:30])[CH:27]=[CH:26][N:25]=2)=[CH:36][CH:37]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(=O)N(Cc1cccc(-c2ccnc(Cl)n2)c1)CC1CCN(C(=O)OC(C)(C)C)C1
Product: CC(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)CC1CCNC1

Procedure:
Intermediate 60 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 446.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[CH:9][C:8]=1[C:21]([F:24])([F:23])[F:22])#[N:6]>>[C:5]([C:7]1[CH:12]=[C:11]([N+:1]([O-:4])=[O:2])[C:10]([NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=[CH:9][C:8]=1[C:21]([F:22])([F:24])[F:23])#[N:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Product: CCOC(=O)C(=O)Nc1cc(C(F)(F)F)c(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To 75 ml ice-cooled 100% nitric acid was added gradually 7.25 g (25.3 mmol) 2-cyano-5-ethoxalylaminobenzotrifluoride. Stirring was continued at 25° C. for 3 h. The reaction mixture was poured into 500 ml ice-water to give a crude product. Recrystallization (ethanol-water) gave 5.1 g (61%) 2-cyano-5-ethoxalylamino-4-nitrobenzotrifluoride. M.p. 101°-102° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][CH:25]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(CC)CC)C>CS(C)=O.O>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:10]3[CH:9]=[C:8]([CH:25]=[CH:24][CH:23]=3)[CH:7]=[C:4]3[CH2:5][CH2:6][N:1]([C:33]([NH:32][C:28]4[N:27]=[N:26][CH:31]=[CH:30][CH:29]=4)=[O:34])[CH2:2][CH2:3]3)=[N:13][CH:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCCC3)cn2)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(N4CCCC4)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.8 %

Procedure:
To a solution of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-(pyrrolidin-1-yl)pyridine (0.118 g, 0.352 mmol) in DMSO (2 mL) was added phenyl pyridazin-3-ylcarbamate (0.076 g, 0.352 mmol) followed by triethylamine (0.048 mL, 0.352 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude compound. The residue was purified by silica gel column chromatography (28% acetone/hexane) to give the title compound (0.125 g, 78% yield). 1H NMR (500 MHz, CDCl3): δ 8.78 (s, 1H), 8.39 (s, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.45 (d, J=4.6 Hz, 1H), 7.27 (m, 2H), 6.95 (m, 1H), 6.92 (m, 2H), 6.84 (m, 2H), 6.38 (s, 1H), 3.69 (m, 2H), 3.58 (m, 2H), 3.27 (m, 4H), 2.59 (m, 2H), 2.45 (m, 2H), 2.03 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 156.56, 153.78, 147.15, 141.50, 138.54, 137.14, 130.50, 129.31, 128.31, 125.21, 123.64, 122.70, 119.41, 117.31, 113.03, 47.85, 45.70, 44.70, 35.76, 29.12, 25.39; m/z (457.1, MH+); HPLC: 97.3%.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NNC(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
4-Methylbenzohydrazide (6 g, 40 mmol) was dissolved in DCM (100 mL) and triethylamine (7.3 g, 80 mmol) was added. The solution was cooled with an ice-bath and ethyl chloro(oxo)acetate (5.5 g, 40 mmol) was added dropwise. After completed addition the reaction was stirred at 0° C. for 1 h and at rt for 2 h. The reaction mixture was washed with 0.2 M HCl, aqueous NaHCO3 solution (sat.) and brine. The organic solution was filtered through a phase separator and the solvent was removed by evaporation. There was obtained 8.1 g (81%) of 6A as a white solid. 1H NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.38 (s, 3H), 4.35 (q, 2H) 7.21 (d, 2H), 7.73 (d, 2H).