Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:12][C@@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][C:9]2=[O:16])=[N:4][N:5]([CH3:7])[CH:6]=1.[C:17]([O:21][C:22]([N:24]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:25]1[CH:30]=[C:29]([C:31]2[O:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=2)[CH:28]=[CH:27][N:26]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH3:15][N:13]([CH3:14])[C@@H:11]1[CH2:12][N:8]([C:3]2[C:2]([NH:1][C:36]([C:34]3[N:35]=[C:31]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([N:24]([CH2:39][C:40]([F:42])([F:41])[F:43])[C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:30]=4)[O:32][CH:33]=3)=[O:37])=[CH:6][N:5]([CH3:7])[N:4]=2)[C:9](=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)O)co2)ccn1
Reactant: CN(C)[C@H]1CC(=O)N(c2nn(C)cc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.3 %

Procedure:
To a solution of (4S)-1-(4-amino-1-methyl-1H-pyrazol-3-yl)-4-(dimethylamino)pyrrolidin-2-one (69.9 mg), 2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylic acid (146 mg) and HATU (143 mg) in DMF (1.57 mL) was added diisopropylethylamine (0.082 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (63.7 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Clc1nc(NCc2cccnc2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(Cl)nc21
Temperature: 70 °C
Yield: 77.8 %

Procedure:
(2-Chloro-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (110.3 g, 0.37 mol) was dissolved in dry DMF (1.5 L) and warmed to 70° C. with stirring. K2CO3 (230 g, 1.67 mol) and 2-bromopropane (300 mL, 3.20 mol) were added and the reaction was stirred at 70° C. overnight. The reaction mixture was allowed to cool to room temperature and K2CO3 was removed by filtration and washing with EtOAc. The combined filtrate and washings were concentrated on a rotary evaporator and then under high vacuum to remove most of the DMF. The resulting residue was stirred vigorously in H2O (1 L) and CH2Cl2 (1 L) until dissolution was complete. The aqueous layer was extracted with more CH2Cl2 (2×200 mL), the organic extracts were combined, dried over MgSO4, and evaporated to afford the title compound (87.2 g, 78%) as a beige powder. 1H-NMR (DMSO-d6): δ1.50-1.53 (6H, d, —CH(CH3)2), 4.67-4.72 (3H, m, —CH2—NH— & —CH(CH3)2), 5.20 (1H, br. s, NH, 7.34-7.39 (dd, ArH), 7.76-7.79 (1H, d, ArH), 8.33 (1H, s, ArH, —N═CH—N—), 8.46-8.48 (1H, d, ArH), 8.61 (1H, s, ArH), 8.92 (1H, br. s, NH.
Reaction SMILES: SC1C(=O)C=CC=CC=1.SC1C2C=CC=CC=2C=CC(=O)C=1.[NH2:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1.[CH2:36]([O:38][C:39](=[O:55])[C:40](SC1C2C=CC=CC=2C=CC(=O)C=1)=[O:41])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:55])[C:40]([NH:23][C:24]1[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[CH:28]=[CH:27][C:26](=[O:35])[CH:25]=1)=[O:41])[CH3:37]
Reactant: CCOC(=O)C(=O)Sc1cc(=O)ccc2ccccc12
Reactant: Nc1cc(=O)ccc2ccncc12
Agent: O=c1ccc2ccccc2c(S)c1
Agent: O=c1cccccc1S
Product: CCOC(=O)C(=O)Nc1cc(=O)ccc2ccncc12

Procedure:
By following serially the procedures of Examples 1 and 2 but replacing 2-mercapto-2,4,6-cycloheptatrien-1-one with an equivalent amount of 5-mercapto-7H-benzocyclohepten-7-one, 9-amino-7H-cyclohepta[c]pyridin-7-one, 5-mercapto-3H-6,7-dihydrocyclobutacyclohepten-3-one, 1-ethylamino-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-3-one and 5-mercapto-3H-6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-3-one, the following compounds are obtained respectively: [(7-oxo-7H-benzocyclohepten-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5, and R6 = H; R2S--CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--CH=CH-- chain), [(7-oxo-7H-cyclohepta[c]pyridin-9-yl)-amino]oxo-acetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = NC2H5 --CO--COOC2H5 ; and R3 and R4 together form a --CH=CH--N=CH-- chain). [(3-oxo-3H-6,7-dihydrocyclobutacyclohepten-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = S--CO--COOC2H5 ; and R3 and R4 together form a --CH2CH2 -- chain), [N-(3-oxo-3H-6,7,8,9,10,11-hexahydrocycloheptacycloocten-1-yl)ethylamino]-oxo-acetic acid ethyl ester (I; R1, R2 and R6 = H; R3 and R4 together form a --(CH2)6 chain; and R5 = NC2H5 --CO--COOC2H5 ) and [(3-oxo-3H- 6,7,8,9,10,11,12,13-octahydrocycloheptacyclodecen-5-yl)thio]oxo-acetic acid ethyl ester (I; R1, R5 and R6 = H; R2 = S--CO--COOC2H5 ; and R3 and R4 together form a --(CH2)8 -- chain).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-])=O)=[C:6]([CH:23]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:23][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(C)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(C)ccc12
Yield: 88.1 %

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-fluoro-2-nitroanilino)-6-methylbenzo[b]thiophene-3-carboxylate (1.9 g), ethyl acetate (200 ml), 10% palladium-carbon (0.4 g) and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-fluoroanilino)-6-methylbenzo[b]thiophene-3-carboxylate (1.54 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N)CCC.[N+:22]([CH2:25][CH2:26][CH3:27])([O-:24])=[O:23]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:25]([N+:22]([O-:24])=[O:23])[CH2:26][CH3:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCC[N+](=O)[O-]
Solvent: CCCCN
Product: CCC(=Cc1ccc(OCc2ccccc2)cc1)[N+](=O)[O-]
Reaction time: 3 h

Procedure:
The starting material is prepared as follows: The mixture of 80 g of p-benzyloxybenzaldehyde, 100 ml of 1-nitro-propane and 5 ml of n-butylamine is placed in a reflux extractor filled with molecular sieves (type 5A), and refluxed for four hours. It is evaporated, the residue dissolved in diethyl ether containing some ethyl acetate and the solution stirred vigorously with a saturated sodium bisulphite solution for three hours. The inorganic layer is washed with ethyl acetate and the combined organic extracts washed with brine, dried and evaporated to afford the 1-(4-benzyloxyphenyl)-2-nitro-1-butene, which is used without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24](=[O:27])[CH2:23]2>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:23]1[C:22]2[C:26](=[C:18]([F:17])[CH:19]=[CH:20][CH:21]=2)[NH:25][C:24]1=[O:27])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2cccc(F)c2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3c(F)cccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 7-fluoro-2-oxindole to give 0.25 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-7-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]2[CH2:13][C:14](=[O:16])[CH2:15][CH:10]2[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:9]1[CH:10]2[CH2:15][C:14](=[O:16])[CH2:13][CH:11]2[CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2CNCC2C1

Procedure:
Reacting starting material 5-oxo-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (I-1a) with trifluoroacetic acid in the solvent of dichloromethane in an ice-water bath to obtain hexahydro-cyclopenta[c]pyrrol-5-one triflutate (I-1b); reacting hexahydro-cyclopenta[c]pyrrol-5-one triflutate (I-1b) with acyl chloride or ester in the presence of base to give the compounds of formula (I-1c); reacting the compounds of formula (I-1c) with equivalent amounts of different amines, sodium triacetoxyborohydride and triethylamine in the solvent of methanol at room temperature to obtain the compounds of formula (IB).
Reaction SMILES: [N+](=[C:3](P(=O)(OC)OC)C(=O)C)=[N-].[NH2:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]=O)=[C:23]([F:29])[CH:22]=2)[N:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[C:15]=1[Cl:34].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:13][C:14]1[C:19]([F:20])=[C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[CH:3])=[C:23]([F:29])[CH:22]=2)[N:17]=[C:16]([C:30]([O:32][CH3:33])=[O:31])[C:15]=1[Cl:34]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: COC(=O)c1nc(-c2ccc(C=O)c(F)c2)c(F)c(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(-c2nc(C(=O)OC)c(Cl)c(N)c2F)cc1F
Temperature: 23 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
Dimethyl 1-diazo-2-oxopropylphosphonate (290 mg, 1.5 mmol, 1.2 equiv) was added to a stirred mixture of methyl 4-amino-3-chloro-5-fluoro-6-(3-fluoro-4-formylphenyl)picolinate (410 mg, 1.3 mmol, 1.0 equiv) and solid potassium carbonate (350 mg, 2.5 mmol, 2.0 equiv) in methanol (12 mL) at 23° C. The resulting cloudy pale yellow mixture was stirred at 23° C. for 2 h. The reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4×60 mL). The organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (33% ethyl acetate in hexanes) to afford the title compound as a white powder (150 mg, 38%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+].O>C(O)C>[N:22]([CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)=[O:4])=[N+:23]=[N-:24]
Reactant: O=C(CCl)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Yield: 58.9 %

Procedure:
A mixture of 2.0 g of 2-chloro-4'-(m-chlorophenylsulfonyl)acetanilide, 0.41 g of sodium azide, 20 ml of water and 40 ml of ethanol was refluxed for 3.5 hours and then evaporated to dryness. The residue was crystallized from ethanol, giving 1.2 g of 2-azido-4'-(m-chlorophenylsulfonyl)acetanilide, mp 125°-126° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:24]=[CH:25][C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:28][C:27]=3[CH:37]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]5[O:30][C:29]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)=[N:28][C:27]=5[CH:37]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1coc(-c2ccc3oc(-c4ccccc4)nc3c2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: c1ccc(-c2nc3cc(-c4nc(COc5ccc(CCCn6ccnc6)cc5)co4)ccc3o2)cc1
Yield: 53 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 5-(4-chloromethyl-2-oxazolyl)-2-phenylbenzoxazole to give 5-[4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-oxazolyl]-2-phenylbenzoxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 166-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1.[CH2:28]1[CH2:32]OC[CH2:29]1.C(COC)OC.[Cl-].C([Zn+])(C)C>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([CH:28]([CH3:32])[CH3:29])=[N:10][N:9]([C:15]3[CH:16]=[C:17]([NH:21][C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:25])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(=O)Nc1cccc(-n2nc(Br)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)[Zn+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)Nc1cccc(-n2nc(C(C)C)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 50 °C
Yield: 58 %

Procedure:
According to Scheme 2 Step 4: A mixture of N-(3-(4-(4-chlorobenzyl)-6-bromo-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide 2(C) (100 mg, 0.22 mmol), THF (2 mL), dimethoxyethane (69 μl, 0.67 mmol) and PdCl2(dppf) (8 mg, 0.011 mmol) was stirred under nitrogen atmosphere at 50° C. Isopropylzinc(II) chloride solution 0.58M (1.15 mL, 0.67 mmol) was added dropwise and the mixture was stirred at 50° C. during 1 hour. The reaction mixture was diluted with 100 mL of water and extracted twice with 100 mL of CH2Cl2. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 15 g SiO2) using AcOEt/cyclohexane 4/6 as eluant to afford a brown solid. The solid was washed with diisopropylether and was filtered to afford N-(3-(4-(4-chlorobenzyl)-6-isopropyl-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenyl)acetamide (53 mg, 58%) as a white solid.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:4].[BrH:15]>C(O)(=O)C>[BrH:1].[Br:15][CH2:4][C:3]([C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc2nc[nH]c2c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2nc[nH]c2c1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
1.21 g (7.6 mmol) of bromine in 5 ml of glacial acetic acid are added to a solution of 1.2 g (7.5 mmol) of 5-acetylbenzimidazole and 1.35 g of 48% strength aqueous HBr (=8 mmol of HB) in 15 ml of glacial acetic acid at room temperature. The mixture is stirred at 40° C. for 30 minutes and cooled and the product which has precipitated out is filtered off.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[C:14](=[N:19]\[S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al]([C:31]#[N:32])(CC)CC.CC(O)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([C:31]#[N:32])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Al](C#N)CC
Reactant: C=CCC/C(=N/[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CCC[C@@](C#N)(N[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A solution of (R,Z)—N-(1-(1-benzylpiperidin-4-yl)pent-4-enylidene)-2-methylpropane-2-sulfinamide (2.74 g, 7.6 mmol) in THF (130 mL, 0.06 M) was cooled to −78° C. Separately, a 1 M solution of Et2AlCN (11.4 mmol, 11.4 mL) was dissolved in THF (20 mL) and cooled to −78° C. iPrOH (0.64 mL, 8.26 mmol) was added dropwise and the solution was warmed to RT over 20 min, then added dropwise to the sulfinamide solution. The reaction was allowed to warm gradually to RT and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and filtered through Celite. The Celite pad was washed with ethyl acetate (3×) and the combined organics were washed saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (1-9% methanol in dichloromethane and again with 2-5% methanol in ethyl acetate) to afford the desired product (1.99 g, 67%) along with its undesired diastereoisomer (0.46 g, 15%). Rf 0.26 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.25 (m, 5H), 5.83-5.78 (m, 1H), 5.13-5.03 (m, 2H), 3.51 (d, J=1.5 Hz, 2H), 3.41 (s, 1H), 3.00 (d, J=11.0 Hz, 2H), 2.34-2.29 (m, 2H), 2.05-1.83 (m, 6H), 1.60-1.44 (m, 3H), 1.25 (s, 9H). ESI MS found for C22H33N3OS m/z [388.4 (M+1)].
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CN=C(C(N)=O)C=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.[Si:26]([O:33][CH2:34][CH2:35][NH:36][C:37]([C:39]1[C:44](Cl)=[CH:43][CH:42]=[CH:41][N:40]=1)=[O:38])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:43]2[CH:42]=[CH:41][N:40]=[C:39]([C:37]([NH:36][CH2:35][CH2:34][O:33][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])=[O:38])[CH:44]=2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1ncccc1Cl
Agent: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
4-(4-Aminophenoxy)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridine-2-carboxamide was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (Intermediate 2C), starting from 4-aminophenol and N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)chloropyridine-2-carboxamide MS ES: 388 (M+H)+, calcd 388, RT=3.60 min.
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=2[C:15]=1[NH2:16])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1OC2C=CC=CC=2C=1N)(=O)C=CC1C=CC=CC=1>>[C:4]1([CH:3]2[NH:16][C:15]3[C:14]4[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:13]=4[O:12][C:11]=3[C:1](=[O:10])[CH2:2]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2oc(C(=O)/C=C/c3ccccc3)c(N)c2c1
Agent: Nc1c(C(=O)C=Cc2ccccc2)oc2ccccc12
Product: COc1ccc2oc3c(c2c1)NC(c1ccccc1)CC3=O

Procedure:
The procedure was similar to step S1C, while the starting material was 4D in stead of 1B.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:39][NH:40][CH3:41]>C(Cl)Cl>[CH3:39][N:40]([CH3:41])[C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8]
Reactant: CNC
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a stirred solution of 3-Fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 6, 0.1 g, 0.196 mmol) in DCM (2 mL) was added oxalyl chloride (0.023 g, 0.193 mmol) at 0° C. Reaction mixture was stirred at room temperature for 1 hour and cooled to 0° C. followed by addition of dimethyl amine (gas) was purged for 2 hours. Resulting reaction mixture was stirred at room temperature for 18 hours. After complete consumption of starting material, reaction mixture was diluted with DCM (3 mL), washed with water (3×3 mL). Organic layer was dried over sodium sulphate and evaporated in vacuo to get crude thick oil (0.077 g). Crude was purified by column chromatography on silica gel (100-200 mesh size), compound was eluted using 2% methanol in DCM and crystallized with chloroform:pentane (1:9) to afford off white solid (0.035 g, 33%). 1H-NMR (400 MHz, CDCl3) δ: 2.79-2.80 (m, 1H), 2.80-2.94 (m, 4H), 2.97 (s, 3H), 2.99 (s, 3H), 3.66-3.69 (m, 1H), 4.07 (d, 1H, J=17.16 Hz), 7.51 (d, 2H, J=8.16 Hz), 7.63-7.65 (m, 4H); LC-MS (m/z): [M−H] 535.0.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]4OCC[O:21]4)=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][CH:15]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ncc2cc(Oc3ccc(C4OCCO4)cc3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(=O)n1ncc2cc(Oc3ccc(C=O)cc3)ccc21
Reaction time: 16 h

Procedure:
1-Acetyl-5-{[4-(1,3-dioxolan-2-yl)phenyl]oxy}-1H-indazole (835 mg, 2.57 mmol) in 25 mL acetone was treated with MP-TsOH (Argonaut, macroporous polymer supported tosic acid, approximately 200 mg, 0.28 mmol) and stirred for 16 hours. The reaction was filtered and concentrated to provide 4-[(1-acetyl-1H-indazol-5-yl)oxy]benzaldehyde quantitatively, which was used without further purification.
Reaction SMILES: N1C2C(=CC=CC=2)C=C[CH:2]=1.[CH:11]([C:14]1[N:15]=[C:16]([C:19]2[CH:28]=[C:27]([O:29][CH:30]3[CH2:48][CH:47]4[N:32]([C:33](=[O:53])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH:42]5[C:44]([C:50]([OH:52])=[O:51])([NH:45][C:46]4=[O:49])[CH2:43]5)[CH2:31]3)[C:26]3[C:21](=[CH:22][C:23]([O:54][CH3:55])=[CH:24][CH:25]=3)[N:20]=2)[S:17][CH:18]=1)([CH3:13])[CH3:12]>>[CH:11]([C:14]1[N:15]=[C:16]([C:19]2[CH:28]=[C:27]([O:29][CH:30]3[CH2:48][CH:47]4[N:32]([C:33](=[O:53])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH:42]5[C:44]([C:50]([OH:52])=[O:51])([NH:45][C:46]4=[O:49])[CH2:43]5)[CH2:31]3)[C:26]3[C:21](=[C:22]([CH3:2])[C:23]([O:54][CH3:55])=[CH:24][CH:25]=3)[N:20]=2)[S:17][CH:18]=1)([CH3:13])[CH3:12]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: c1ccc2ncccc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from quinoline 28 and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=647 (M+H)+.