Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>>[C:16]([NH:20][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 74.2 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), tert-butylamine (503 mg, 6.88mmol) and triethylamine(l.43 mL, 10.32 mmol) were reacted to form the desired product (1.67 g, 75%). 1H NMR (MeOD-d4): δ 7.91 (d, 1H), 7.78 (d, 1H), 1.25 (s, 9H).
Reaction SMILES: [CH2:1]=O.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10]>O.C(OC(C)C)(C)C>[S:10]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:1]1
Reactant: Nc1ccccc1S
Reactant: C=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: c1ccc2c(c1)NCS2
Reaction time: 0.5 h

Procedure:
37% formalin (5.2 mL) was diluted with water (80 mL), and diisopropylether (80 mL) and 2-aminobenzenethiol (7.84 g) were added, and then the mixture was stirred at mom temperature for 30 minutes. The organic layer was separated and the aqueous layer was extracted with diisopropylether. The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (c).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16]([O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:25]([C@@H:27]1[C@@H:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:30][N:29]([C@H:38]([CH:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[C:39]([O:41]CC2C=CC(OC)=CC=2)=[O:40])[CH2:28]1)=O>>[CH2:8]([NH:15][C:16]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C@@H:27]2[C@@H:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:30][N:29]([C@H:38]([CH:51]3[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)[C:39]([OH:41])=[O:40])[CH2:28]2)[CH2:21][CH2:20]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: O=C(NCc1ccccc1)OC1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccccc1)OC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1
Yield: 63.7 %

Procedure:
The title compound was prepared from 4-((N-benzylcarbamoyl)oxy)-piperidine trifluoroacetate (35 mg, 0.1 mmol, from Step B) and (R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-(methoxy)benzyl ester (25 mg, 0.05 mmol, Aldehyde 5) according to the method described in Example 1, Step C to give 17 mg (64%) of the title compound. ESI-MS: 534.5 (M+H); HPLC A: 2.16 min.
Reaction SMILES: C[O-].[Na+].C([S:7][C@@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:41])[CH2:23][NH:24][C:25]([NH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])=[NH:26])[CH2:17]2)=[O:15])[CH2:9]1)(=O)C.Cl>CO>[SH:7][C@@H:8]1[CH2:12][N:11]([CH3:13])[C@H:10]([C:14]([N:16]2[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:41])[CH2:23][NH:24][C:25]([NH:27][C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:29])=[NH:26])[CH2:17]2)=[O:15])[CH2:9]1
Reactant: CC(=O)S[C@H]1C[C@@H](C(=O)N2CC[C@H](NC(=O)CNC(=N)NC(=O)OCc3ccc([N+](=O)[O-])cc3)C2)N(C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](S)C[C@H]1C(=O)N1CC[C@H](NC(=O)CNC(=N)NC(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
A solution of 28% sodium methylate in methanol (0.5 ml) was added to a solution of (2S,4S)-4-acetylthio-1-methyl-2-[(3S)-3-[2-[3-(4-nitrobenzyloxy-carbonyl)guanidino]acetylamino]pyrrolidin-1-ylcarbonyl]pyrrolidine (1.5 g) in methanol (30 ml) and stirred at room temperature for 1 hour. At the end of this time, to the resulting mixture was added 1N hydrochloric acid (2.73 ml) and concentrated in vacuo. The resulting residue was chromatographed on a reverse phase column (Cosmosil 75C18PREP (trade mark) manufactured by Nacalai tesque Inc.) using a mixture of acetonitrile and water as the eluant. The fractions containing the desired product were combined and concentrated in vacuo. The residue was powdered in a mixture of ethyl acetate and isopropyl ether. Powdery (2S,4S)-4-mercapto-1-methyl-2-[(3S)-3[2-[3-(4-nitrobenzyloxycarbonyl)guanidino]acetylamino]pyrrolidin-1-yl-carbonyl]pyrrolidine (806 mg) was obtained by filtration.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=3)[NH:7][CH:6]=2)[CH2:27][CH2:28]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCBr)c2c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2[nH]cc(CCCN3CCN(c4ccccn4)CC3)c2c1
Yield: 39.1 %

Procedure:
A mixture of 3-[3-bromopropyl]-5-nitro-1H-indole (1.4 g, 4.2 mmol), 1-(2-pyridinyl)-piperazine, (0.98 g, 5.09 mmol) and K2CO3 (1.4 g, 10.2 mmol) in 30 mL of acetonitrile was heated to reflux for 4 h. The reaction mixture was cooled, the solvent was removed and the residue dissolved in ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The organic extracts were dried (MgSO4) and concentrated, and the gummy residue purified by flash silica gel chromatography (5% methanol in dichloromethane) to give 3-[3-[4-(2-pyridinyl)-1-piperazinyl]propyl]-5-nitro-1H-indole, (0.6 g, 36%) as a yellow solid: IR(KBr) 3182, 1520, 1330 cm-1 ; 1H NMR (DMSO-d6, 300 MHz) δ8.52 (d, J=2.24 Hz, 1H), 8.80 (dd, J=1.8, 4.8 Hz, 1H), 7.95 (dd, J=2.25, 9.0 Hz, 1H), 7.52-7.49 (m, 2H), 7.41 (s, 1H), 6.79 (d, J=8.6 Hz, 1H), 6.60 (t, J=6.6 Hz, 1H), 3.46 (t, J=4.7 Hz, 4H), 2.78 (t, J=7.4 Hz, 2H), 2.42 (t, J=5.0 Hz, 4H), 2.34 (t, J=6.9 HZ, 4H), 1.82 (dt, J=7.4, 6.9 Hz, 2H); MS (m/e) 365 (M+). Anal. Calcd for C20H23N5O2 : C, 65.73, H, 6.34, N 19.16; found C, 65.35, H, 6.26, N, 18.87.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[N:17][C:18](Cl)=[C:13]3[C:12]([Br:20])=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CCN(C(C)C)C(C)C>CC(O)C>[C:24]([O:23][C:21]([N:28]1[CH2:33][CH2:32][N:31]([C:18]2[N:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[N:11]=[C:12]([Br:20])[C:13]=23)[CH2:30][CH2:29]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1nc(Br)c2c(Cl)ncnc21
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2c(Br)nn3S(=O)(=O)c2ccccc2)CC1
Temperature: -10 °C
Yield: 67.7 %

Procedure:
A solution of 1-Benzenesulfonyl-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (1.8 g, 4.8 mmol), Boc-piperazine (1.4 g, 7.2 mmol) and DIPEA (2.1 mL, 12 mmol) in IPA (40 mL) was stirred and heated at reflux overnight. The reaction mixture was cooled to −10° C., the solids isolated by vacuum filtration, rinsed with cold IPA and dried further on high vacuum line to give 4-(1-Benzenesulfonyl-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.7 g, 67%) as a white powder. LCMS (APCI+) m/z 523 and 525 [M+H]+; Rt: 3.57 min. 1H NMR (CDCl3, 400 MHz) δ 8.53 (1H, s), 8.23 (2H, d, J 8.5 Hz), 7.65 (1H, t, J 6.9 Hz), 7.54 (2H, t, J 7.8 Hz), 3.82-3.79 (4H, m), 3.60-3.57 (4H, m), 1.48 (9H, s.)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH:21][C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCN(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A 100 mL round bottom flask was dried in an oven overnight and cooled to room temperature under Ar(g). The flask was charged with fluoronitrobenzene (0.187 mL, 1.77 mmol), 3-(4-Methyl-piperazin-1-yl)-propylamine (0.361 g, 2.30 mmol) and dioxane (9.0 mL). To the resulting solution diisopropyl ethyl amine (0.463 mL, 2.66 mmol) was added dropwise and allowed to stir at 105° C. for 48 h. The mixture was extracted with EtOAc (3×˜30 mL), and with brine (2×˜30 mL). The combined organic layers were then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude mixture was then purified over silica (10% MeOH/90% CHCl3) affording a yellow solid (0.365 g, 1.31 mmol, 74% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][CH:13]=[C:14]([CH:16]=O)[N:15]=1)[CH2:2][CH3:3].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[NH:19][NH2:20]>>[CH2:23]([O:22][C:18](=[O:21])[NH:19][N:20]=[CH:16][C:14]1[N:15]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[NH:12][CH:13]=1)[CH3:24]
Reactant: CCCOc1ccccc1-c1nc(C=O)c[nH]1
Reactant: CCOC(=O)NN
Product: CCCOc1ccccc1-c1nc(C=NNC(=O)OCC)c[nH]1

Procedure:
A 4.3 gm. portion of 2-o-propoxyphenyl-4-imidazolecarboxaldehyde and 1.98 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 129°-132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[Cl:21][C:22]1[N:27]=[N:26][C:25]([C:28](Cl)=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:28]([C:25]3[N:26]=[N:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[O:29])[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(Cl)c1ccc(Cl)nn1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nn1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a solution of 1-(6-chloronaphthalen-2-ylsulfonyl)-piperazine (0.450 g, 1.45 mmol) in methylene chloride (100 mL) and pyridine (0.154 mL) was added dropwise 6-chloropyridazine-3-carbonyl chloride (1.74 mmol). After the addition of the acid chloride, pyridine (0.154 mL) was added, and the reaction mixture was stirred overnight. The reaction mixture was diluted with chloroform (500 mL), washed with saturated sodium bicarbonate (200 mL), water (200 mL),and brine and dried over MgSO4. After filtration and evaporation of the solvent, trituration of the residue with ethyl acetate and filtration gave the product as a white powder (0.5 g, 76%)
Reaction SMILES: [K].[NH2:2][C:3]1[C:8]([C:9]([O-:11])=O)=[CH:7][N:6]=[C:5]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:56][C:57]1[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][CH:58]=1.CN1CCOCC1>CN1C(=O)CCC1.O>[F:56][C:57]1[CH:63]=[CH:62][C:60]([NH:61][C:9]([C:8]2[C:3]([NH2:2])=[N:4][C:5]([SH:12])=[N:6][CH:7]=2)=[O:11])=[CH:59][CH:58]=1
Reactant: Nc1nc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)ncc1C(=O)[O-]
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: Nc1nc(S)ncc1C(=O)Nc1ccc(F)cc1
Reaction time: 12 h
Yield: 490 %

Procedure:
Solid portions of potassium-4-amino-2-tritylsulfanylpyrimidine-5-carboxylate (46 g, 10 mmol) followed by HATU (39 g, 0.10 mol) were added, at ambient temperature, to a solution of 4-fluoroaniline (11 g, 0.10 mol) and NMM (31 g, 0.30 mol) in NMP (500 mL). After stirring for 12 hours, the resulting orange solution was poured into water (1000 mL) and the oily, solid precipitant was collected, dissolved in dichloromethane (500 mL), and diluted with acetic acid (50 mL). The resulting solution was stirred (ambient temperature, 3 h), then concentrated in vacuo (to about 150 mL total volume) and diluted with diethyl ether (100 mL). The resulting yellow solid was collected, washed with dichloromethane and dried in vacuo to afford the titled compound (13 g, 49 mmol, 49% yield). 1H NMR (300 MHz, CD3OD) δ 8.20 (s, 1H), 7.58 (dd, J=9.3, 4.8 Hz, 2H), 7.07 (app. t, J=9.0 Hz, 2H); MS (+APCI) m/z 265 (MH+, 100).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:29][C:30]1[CH:38]=[CH:37][C:36]2[C:35](=O)[CH2:34][CH2:33][C:32]=2[C:31]=1[C:40]#[N:41].[NH4+].[Cl-]>C1COCC1>[F:29][C:30]1[CH:38]=[CH:37][C:36]2[C:35](=[CH:2][O:3][CH3:4])[CH2:34][CH2:33][C:32]=2[C:31]=1[C:40]#[N:41]
Reactant: N#Cc1c(F)ccc2c1CCC2=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC=C1CCc2c1ccc(F)c2C#N

Procedure:
To a suspension of (METHOXYMETHYL)TRIPHENYLPHOSPHONIUM CHLORIDE (1.3 g, 3.8 mmol) in THF (15 ml) was dropped n-Butyl Lithium (3.85 ml, 3.85 mmol) at −20° C. The mixture was stirred for 20 minutes before a THF solution of 5-Fluoro-1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (450 mg, 2.6 mmol) was added into the reaction. TLC showed some green color spot right away. The reaction was then poured into NH4Cl, extracted with EtOAc, and flashed through silica gel. LC-MS (1E, m/z): 204 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:12]([O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:25][CH:26]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl
Product: O=C(O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1

Procedure:
2-(4-Benzyloxyphenylamino)benzoic acid [X; R=H, OR°=4-OCH2C6H5, R"=H] was prepared from 2-chlorobenzoic acid and 4-benzyloxyaniline hydrochloride according to the procedure of Example 1A, part (a), and the crude product was used directly in the following reaction.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=O.C(O)(=O)C>C(#N)C>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=1)=[C:19]2[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CC#N
Solvent: CC(=O)O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 81.5 °C

Procedure:
4-Benzyloxy phenyl hydrazine hydrochloride (1.0 g, 4 mmol), 4-benzyloxy propiophenone (0.96 g, 4 mmol) and acetic acid (10 μl, 0.17 mmol) were suspended in 15 ml of acetonitrile and the mixture was refluxed for 12 hrs at a temperature of 81-82° C. Then mixture was cooled to 10-15° C. within 1 hr. The white product was filtered and washed with chilled acetonitrile (3 ml). 5-Benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-1H-indole (1) melting at 149-150° C. was obtained in a yield of 1.0 g (60%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:26])=[CH:22]B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(=O)(O)[O-].[Na+].O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][NH:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH:20]=[C:21]([CH3:26])[CH3:22])[N:7]=2)=[CH:14][CH:15]=1
Reactant: CC(C)(CNc1cccc(Br)n1)c1ccc(F)cc1
Reactant: CC(C)=CB(O)O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)=Cc1cccc(NCC(C)(C)c2ccc(F)cc2)n1
Temperature: 135 °C
Yield: 6.7 %

Procedure:
To a 5 mL microwave reaction vessel was added 6-bromo-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridin-2-amine (220 mg, 0.7 mmol, 1.0 equiv), 2-methylprop-1-enylboronic acid (100 mg, 1 mmol, 1.5 equiv), Cl2Pd(dppf) (50 mg, 70 μmol, 0.1 equiv), potassium carbonate (300 mg, 2.1 mmol, 3.0 equiv), dioxane (4 mL), and water (1 mL). The reaction was heated in a microwave reactor at 135° C. for 35 min and then diluted with saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 14 mg of N-(2-(4-fluorophenyl)-2-methylpropyl)-6-(2-methylprop-1-enyl)pyridin-2-amine (m/z [M+H]=299.4).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[O:18][CH3:19])([OH:6])[CH2:3]1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]2([OH:6])[CH2:5][C:2]([F:20])([F:1])[CH2:3]2)=[C:10]([O:18][CH3:19])[CH:11]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC1(O)CC(F)(F)C1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1OCC1(O)CC(F)(F)C1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A mixture of 3,3-difluoro-1-((2-methoxy-4-nitrophenoxy)methyl)cyclobutanol (32.0 g, 111 mmol) prepared in Part F and 10% Pd/C (2.0 g, 1.879 mmol) in 700 mL MeOH was stirred under H2 at 50 psi for 1.5 h. After filtration, the filtrate was concentrated to give 1-((4-amino-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutanol (28.9 g, 111 mmol, quantitative yield) as a light purple solid. 1H NMR (400 MHz, CD3OD) δ ppm 6.68 (1H, d, J=8.56 Hz), 6.35 (1H, d, J=2.52 Hz), 6.16 (1H, dd, J=8.31, 2.52 Hz), 4.77 (3H, br. s.), 3.78 (2H, s), 3.68 (3H, s), 2.68-2.82 (2H, m), 2.38-2.56 (2H, m).
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH:11]=1.CO[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1>C1COCC1>[CH3:29][C:24]1([CH3:30])[C:25]([CH3:28])([CH3:27])[O:26][B:22]([C:7]2[CH:8]=[N:9][N:10]([CH:12]3[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]3)[CH:11]=2)[O:23]1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: O=S1(=O)CCC(n2cc(I)cn2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C3CCS(=O)(=O)CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Isopropylmagnesium chloride (2.0 M in THF, 1.23 mL, 2.45 mmol) was slowly added to a solution of 4-(4-iodo-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide (0.50 g, 1.533 mmol) in THF (6.0 mL) at −10° C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction was then cooled to 0° C., 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.402 mL, 2.45 mmol) was added, and the reaction stirred at room temperature for an additional 1.5 h. The reaction solution was then concentrated in vacuo to remove the THF. The crude solid was dissolved in ether (200 mL) and filtered. The filtrate was slowly concentrated until a white precipitate formed. The solution was allowed to stand for 2 h, and the precipitate was filtered and dried in vacuo to afford 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)tetrahydro-2H-thiopyran 1,1-dioxide (0.34 g, 68%) as a white powder. MS (ESI, pos. ion) m/z 327 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][N:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[C:4]=1[CH3:21]
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Reactant: FC(F)(F)c1ccc(Br)cc1
Product: COc1c(C)c(N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 59.7 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (436 mg, 1.50 mmol) synthesized in Reference example 96 and 1-bromo-4-(trifluoromethyl)benzene (506 mg, 2.25 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 389 mg (yield 40%). Melting point was 186 to 187° C. (hexane).
Reaction SMILES: C(OC([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl.CCOC(C)=O.O>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:24]2[CH2:25][CH2:26][C@@H:22]([NH:8][C:9]3[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=3)[CH2:23]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(OC)cc3)C2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C=C/c1ccc(N[C@@H]2CCN(Cc3ccc(OC)cc3)C2)nc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
To an ice-cooled solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (360 mg) in dichloromethane (2 ml) was added anisole (11.0 ml) and TFA (2.0 ml), the mixture was stirred at 20° C. for 1 hour. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). The pH of the aqueous layer was adjusted to ca. 9 with NaHCO3. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give ethyl (2E)-3-(6-{[(3R)-1-(4-methoxybenzyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate as syrup (295 mg).