Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[N:9]([CH3:18])[N:10]=[C:11]2[C:16]=1[C:15]([OH:17])=[CH:14][CH:13]=[CH:12]2)(=[O:7])=[O:6].[H-].[Na+].Br[CH2:23][CH2:24][F:25]>CN(C=O)C>[CH3:1][N:2]([CH3:19])[CH:3]=[N:4][S:5]([C:8]1[N:9]([CH3:18])[N:10]=[C:11]2[C:16]=1[C:15]([O:17][CH2:23][CH2:24][F:25])=[CH:14][CH:13]=[CH:12]2)(=[O:6])=[O:7]
Reactant: CN(C)C=NS(=O)(=O)c1c2c(O)cccc2nn1C
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)c1c2c(OCCF)cccc2nn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
4.2 g (15 mmol) of N1,N1 -dimethyl-N2 -[(4-hydroxy-2-methyl-2H-indazol-3-yl)sulfonyl]formamidine was added to a suspension containing 0.6 g (15 mmol) of 60% sodium hydride in 50 ml of DMF, and the mixture was stirred at room temperature for one hour. Further, 2 g (16 mmol) of 1-bromo-2-fluoroethane was added thereto, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into ice water, and the formed crystals were collected by filtration and washed with water and IPE to obtain the desired product. This product was used for the subsequent reaction without purification. Obtained amount: 3.4 g (yield: 69.5%)
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>C(Cl)Cl>[C:3]1([CH:2]2[CH2:1][CH:11]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccccc1
Reaction time: 1 h

Procedure:
A solution of CH2Cl2 (12.5 mL), styrene (12 5 mL) and ethyl diazoacetate (0.25 g, 2.19 mmol) was added slowly dropwise at ambient temperature to a stirred slurry of Rh-PFIEP[SO3H] (1.0 g, 0.387 mmol, prepared as described above), styrene (2.5 mL) and CH2Cl2 (2.5 mL). Gas evolution ceased about 1 hour after the addition of the ethyl diazoacetate solution was complete. The resulting slurry was stirred for 24 hours and then allowed to settle. The solution was removed, the resulting resin was washed with 3.0 mL of CH2Cl2. The solution and the wash were combined and analyzed for cyclopropane products. Yield (based on ethyl diazoacetate): 73.9%.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][C@H:25]1[O:30][C@@H:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>>[CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:18][CH2:19][CH:20]([N:27]5[CH2:26][C@H:25]([CH3:24])[O:30][C@H:29]([CH3:31])[CH2:28]5)[CH2:21][CH2:22]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: C[C@@H]1CN(C2CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)C[C@H](C)O1
Yield: 59 %

Procedure:
Using a procedure similar to that described in Example 82, except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone and employing cis 2,6-dimethylmorpholine, the title compound was formed in 59% yield as a white solid, mp >300° C. (dec). free base: NMR (CDCl3, 250 MHz) 7.22 (m, 2H), 7.14 (m, 2H), 6.92 (m, 4H), 4.24 (s, 1H), 3.63 (m, 2H), 3.36 (s, 2H), 3.05 (br d, J=11.7 Hz, 2H), 2.71 (d, J=10.5 Hz, 2H), 2.56 (d, J=1.2 Hz, 2H), 2.18 (m, 3H), 1.87 (t, J=10.8 Hz, 2H), 1.73 (m, 2H), 1.52 (dt, J=3.6, 11.9 Hz, 2H), 1.14 (d, J=6.3 Hz, 6H) MS (CI, CH4) m/z 403 (M+1,100), 431 (M+29,21), 287 (45) hydrochloride salt:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3].[CH3:12][O-:13].[Na+]>CN(C)C=O>[CH3:8][C:7]([CH:6]=[CH:5][CH2:4][CH:2]([CH3:1])[CH2:3][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])=[CH:9][C:10]([O:13][CH3:12])=[O:11]
Reactant: CC(C)CCCC(C)CC=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=C(C)C=CCC(C)CCCC(C)C
Reaction time: 2 h

Procedure:
To a mixture of 1.5 g. of dihydrocitronellal, 2.7 g. of diethyl 3-ethoxycarbonyl-2-methylprop-2-enyl phosphonate and 5 ml. of dimethylformamide, under nitrogen and at 0°, with stirring, is added slowly sodium methoxide (250 mg. sodium and 5 ml. of methanol). After addition is complete, the reaction is left two hours at room temperature and then worked up by extraction with ether/hexane to yield methyl 3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])=[CH:8][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CNC[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
A solution of (R)-(−)-1-amino-2-propanol (9.00 g, 0.12 mol) in tetrahydrofuran (40 ml) and acetic acid (5 ml) was added dropwise to a solution of p-anisaldehyde (5.45 g, 0.04 mol) in tetrahydrofuran (40 ml), and once addition was complete, the solution was stirred at room temperature for 2 hours. The solution was cooled in an ice-bath, and sodium triacetoxyborohydride (9.50 g, 0.0.045 mol) was added portionwise, and then the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (150 ml) and sodium hydroxide solution (150 ml, 0.5N). The layers were separated and the aqueous phase was saturated with sodium chloride, then extracted with further dichloromethane (3×30 ml). The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (gradient elution 98:2:0.2 to 97:3:0.3 dichloromethane:methanol:0.88 NH3) to afford an orange oil (4.9 g). 1H-NMR (CDCl3, 400 MHz) δ: 1.12 (d, 3H), 2.39 (dd, 1H), 2.70 (dd, 1H), 3.62-3.79 (m, 6H), 6.82 (d, 2H), 7.19 (d, 2H). LRMS: m/z (ES+) 196 [MH+].
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH3:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29]O)[O:26][C:25]4=[O:31])=[CH:20][C:19]=3[F:32])=[CH:14][N:13]=2)=[N:10][N:11]=1>>[CH3:6][C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:28][C@H:27]([CH2:29][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[O:26][C:25]4=[O:31])=[CH:20][C:19]=3[F:32])=[CH:14][N:13]=2)=[N:10][N:11]=1
Reactant: c1c[nH]nn1
Reactant: Cc1nnc(-c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3F)cn2)o1
Product: Cc1nnc(-c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)o1

Procedure:
The same procedure as in Example 24 was conducted, except for adding 1,2,3-triazole and using the compound 16 as a starting material, to obtain the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[C:15]([S:16][CH3:17])=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:22]O>>[F:6][C:7]1[C:15]([S:16][CH3:17])=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:22])=[O:10]
Reactant: CO
Reactant: CSc1c(C(F)(F)F)ccc(C(=O)O)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C(F)(F)F)c(SC)c1F

Procedure:
5 ml of concentrated sulfuric acid were added to 20.0 g (78.7 mmol) of 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoic acid in 200 ml of methanol, and the mixture was heated under reflux until HPLC analysis showed complete conversion. The mixture was cooled and the solvent was removed. The residue was taken up in water, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous NaHCO3 solution. Finally, the organic phase was dried and the filtrate was concentrated. This gave 20.5 g of methyl 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)cnc2C1

Procedure:
Following the same procedure as described in example 31.5, a portion of crude N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)-propionamide (100 mg, 0.45 mmol) in CH2Cl2/pyridine 9/1 (20 ml) was treated with 4-isopropylbenzenesulfonyl chloride (130 μl, 0.72 mmol). Purification by flash column chromatography (CH2Cl2:methanol, 97:3) gave the title compound (85 mg, 47% for steps 31.4 and this step) as a gum.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7](CCS)=[N:6][S:5](=[O:12])(=[O:11])[N:4]=1.[CH3:13][N:14]([CH2:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22]O)[N:21]=1)[CH3:15]>Cl>[CH3:13][N:14]([CH2:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][S:18][CH2:17][CH2:16][NH:14][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:11])(=[O:12])[N:6]=2)[N:21]=1)[CH3:15]
Reactant: CNC1=NS(=O)(=O)N=C1CCS
Reactant: CN(C)Cc1nc(CO)cs1
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D] in concentrated hydrochloric acid, and then made basic and worked up, produces the title compound which is identical to the product prepared in Example 33.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[C:18]([CH3:29])[N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1.[CH3:32][C:33]1[N:34]([C:38]2[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=2)[C:41](O)=[O:42])[CH:35]=[CH:36][N:37]=1>>[CH3:32][C:33]1[N:34]([C:38]2[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=2)[C:41]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([N:20]3[C:15]4[N:16]([N:17]=[C:13]([C:11]5[CH:12]=[N:8][NH:9][CH:10]=5)[CH:14]=4)[C:18]([CH3:29])=[CH:19]3)[CH:22]=2)=[O:42])[CH:35]=[CH:36][N:37]=1
Reactant: Cc1nccn1-c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)cc(C)n4n3)cn2)cc1
Product: Cc1ccc(NC(=O)c2cc(-n3ccnc3C)cc(C(F)(F)F)c2)cc1-n1cc(C)n2nc(-c3cn[nH]c3)cc12

Procedure:
70 mg (0.17 mmol) of the compound of Example 9A and 50 mg (0.19 mmol) of 3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid [lit.: WO 2004/005281-A1, Example 91b] were reacted analogously to the procedure of Example 13. This gave 58 mg (71% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OCc1ccc(C(F)(F)F)cc1
Product: O=[N+]([O-])c1cnccc1OCc1ccc(C(F)(F)F)cc1
Yield: 89.5 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 4-trifluoromethylbenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 89.5%)
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=NN=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][C@@H:18]([N:20]([C:25]([C:27]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:30]3[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=3[N:28]=2)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][C@@H:16]([C:42](O)=[O:43])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].C1CCC(N=C=NC2CCCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:30]2[CH:38]=[CH:39][CH:40]=[CH:41][C:29]=2[N:28]=[C:27]1[C:25]([N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@H:18]1[CH2:17][C@@H:16]([C:42]2[O:43][C:2]([CH3:1])=[N:6][N:5]=2)[CH2:15][N:14]([C:12]([O:11][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:13])[CH2:19]1)=[O:26]
Reactant: Cc1nnn[nH]1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nnc(C)o3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 100 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
Methyltetrazole (63 mg) and (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (265 mg) were dissolved in toluene (5 ml), DCC (155 mg) was added and the mixture was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, filtered and the solvent of the mother liquor was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=O.S([O-])([O-])(=O)=O.[Mg+2].[CH3:21][NH2:22]>C1C=CC=CC=1>[CH3:21][NH:22][CH2:8][CH:7]=[CH:6][C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CN
Reactant: COc1ccc(C=CC=O)cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: CNCC=Cc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: To the mixture of 19.2 g of 3,4-dimethoxycinnamaldehyde, 24 g of magnesium sulfate and 100 ml of benzene, 6.2 g of methylamine in 120 ml of benzene are added and the suspension is stirred at room temperature for 8 hours. It is filtered and the filtrate added dropwise to the solution of 3.8 g of sodium borohydride in 200 ml to anhydrous ethanol while stirring and cooling with ice. Stirring is continued over night at room temperature, the mixture cooled again, 25 ml of concentrated hydrochloric acid are added and the solution evaporated under reduced pressure. The residue is taken up in 150 ml of water the solution washed with diethyl ether, made basic with sodium hydroxide and the mixture extracted with diethyl ether. The extract is dried and evaporated, to yield the N-methyl-3,4-dimethoxycinnamylamine as an oil; the cyclamate thereof melts at 145°-147°.
Reaction SMILES: [CH3:1][N:2]([C@@H:12]1[C@H:17]([CH3:18])[CH2:16][CH2:15][NH:14][CH2:13]1)[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12.O=C1CCC(=O)N1[O:26][C:27](=O)[CH2:28][C:29]#[N:30].C(O)C>>[CH3:18][C@@H:17]1[CH2:16][CH2:15][N:14]([C:27](=[O:26])[CH2:28][C:29]#[N:30])[CH2:13][C@@H:12]1[N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]=12
Reactant: C[C@@H]1CCNC[C@@H]1N(C)c1ccnc2[nH]ccc12
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: CCO
Product: C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)c1ccnc2[nH]ccc12
Reaction time: 8 h
Yield: 182.5 %

Procedure:
A mixture of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine (43.0 mg, 0.000176 mol) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (38 mg, 0.00021 mol) in ethanol (1 mL, 0.02 mol) was stirred overnight. The reaction mixture was partitioned between ethyl acetate/THF and sat. NaHCO3, and the organic layer was washed by sat. NaCl. The solvent was removed under vacuum to give 100 mg of an orange solid which was chromatographed with 7% MeOH/DCM, 0.7% NH4OH to give 17 mg of pale orange solid. The crude product was triturated with Et2O and the resulting solid was filtered and washed to give 9.4 mg of wet pale orange solid which was dried at from room temperature to about 60° C. for 3.5 h to give 6.5 mg of the final product.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[S:13][C:14]([C:16]([N:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])[CH3:19])=[O:17])=[CH:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:27]=1.CCN(C(C)C)C(C)C.[CH2:37]([N:39]=[C:40]=[O:41])[CH3:38].[Cl-].[NH4+]>C1COCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]([CH3:19])[C:16]([C:14]1[S:13][C:12]2[C:6]3[CH:5]=[CH:4][C:3]([NH:2][C:40]([NH:39][CH2:37][CH3:38])=[O:41])=[CH:27][C:7]=3[O:8][CH2:9][CH2:10][C:11]=2[CH:15]=1)=[O:17]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(N)cc1OCC2)c1ccccc1Cl
Reactant: CCN=C=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 40 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of 8-amino-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide HCl salt (0.25 g, 0.593 mmol) in anhydrous THF (15 mL) was added DIPEA (0.52 mL, 2.97 mmol) and ethyl isocyanate (0.1 g, 1.4 mmol). The solution was stirred at 40° C. overnight. The reaction mixture was poured into ammonium chloride aqueous solution and extracted with EtOAc. The organic phase was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated to the crude product, which was purified by preparative TLC to afford about 0.113 g of 166 (isolated yield: 42%). 1H NMR (DMSO-d6, 400 MHz): δ 8.56 (s, 1H), 7.64-7.58 (m, 2H), 7.49 (t, J=3.6 Hz, 2H), 7.22 (d, J=4.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.92 (dd, J=2.0, 8.4 Hz, 1H), 6.44 (s, 1H), 6.13 (t, J=5.6 Hz, 1H), 4.09 (d, J=4.4 Hz, 2H), 3.22 (s, 3H), 3.06 (dd, J=6.0, 7.2 Hz, 2H), 2.85 (s, 2H), 1.01 (t, J=7.2 Hz, 3H). MS: (ESI+) 456.1
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][N:19]([CH3:26])[C:20](=[O:25])[O:21][CH:22](Cl)[CH3:23])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27]([OH:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([O:35][CH:22]([O:21][C:20]([N:19]([CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH3:26])=[O:25])[CH3:23])=[O:34])[CH:29]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(Cl)OC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(OC(=O)c1cccnc1)OC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Yield: 38.9 %

Procedure:
Following the general procedure of Example 52, but using 1.05 g (0.0028 mol) of the product of Example 51, 0.45 g (0.036 mol) of nicotinic acid and 0.36 g of triethylamine in 10 mL dimethylformamide and carrying out the reaction at 25°-30° C. for 48 hours, gave 0.5 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[N:18]1([CH2:23][CH2:24][CH:25](O)[CH3:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:25]([CH3:26])[CH2:24][CH2:23][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(O)CCN1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CCN1CCCC1)Oc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 9.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (1.03 g, 4.40 mmol), 4-pyrrolidin-1-yl-butan-2-ol (0.5 g, 3.50 mmol), PPh3 (1.15 g, 4.40 mmol), THF (10 ml) and DIAD (0.86 ml, 4.40 mmol) were reacted together according to general procedure C. The crude product was purified by preparative HPLC, eluting with acetonitrile/water/0.1% TFA as a gradient, to give the title compound as a yellow oil (125 mg, 10%). 1H NMR (400 MHz, CDCl3) δ7.19 (d, 2H), 6.86 (d, 2H), 4.43 (m, 1H), 3.75 (dt, 2H), 3.60-3.51 (m, 2H), 2.67-2.46 (m, 6H), 2.40 (s, 2H), 2.14-2.04 (m, 2H), 1.97 (s, 6H), 1.93-1.73 (m, 8H), 1.31 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].[H-].[Na+].Cl>CC(N(C)C)=O>[F:11][C:12]([F:16])([F:15])[CH2:13][O:14][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(OCC(F)(F)F)nc1
Temperature: 90 °C
Reaction time: 21 h
Yield: 77.8 %

Procedure:
A mixture of 6-chloronicotinic acid (7.0 g, 44.4 mmol), 2,2,2-trifluoroethanol (6.40 mL, 89.0 mmol) and sodium hydride (5.33 g, 133.0 mmol, 60% in oil) in DMA (400 mL) is stirred at 90° C. for 21 hours. After cooling to rt, the reaction mixture is poured slowly into 2M hydrochloric acid (300 mL) and extracted with n-hexane/EtOAc (1:10, 500 mL). The organic layer is washed with 2 M hydrochloric acid (300 mL×2) and dried over sodium sulfate. The organic solvent is concentrated under reduced pressure to give 7.64 g (78% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-2) without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[C:11](C)(C)[C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC#N.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccc(OC)cc1

Procedure:
To a solution of 4-methoxyphenol (500 mg, 4.03 mmol) in CH3CN (10 mL) was added ethyl 2-bromo-2-methylpropanoate (807 mg, 4.84 mmol) and K2CO3 (3 g, 21.7 mmol) at 25° C. The mixture was refluxed for 16 h. The mixture was then diluted with water (100 mL), extracted with ethyl acetate (2×50 mL) and the combined organic layers washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.