Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][CH2:11][N:12]([CH3:29])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:31]=O>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]([CH3:30])[CH2:9][CH2:10][CH2:11][N:12]([CH3:29])[C:13]([C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH3:31])[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:20]=1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Reactant: C=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCN(C)c1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 69.3 %

Procedure:
The compound (239 mg, 0.57 mmol) obtained in Example 94a was dissolved in methanol (15 mL), paraformaldehyde (179 mg, 5.67 mmol) and 10% palladium-carbon (48 mg, 20% by weight) were added, and the mixture was stirred at 60° C. under a hydrogen atmosphere for 18 hours. After the reaction was completed, the reaction mixture was filtered through celite, the filtrate was washed with methanol, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 10:1, v/v) to give the title compound (172 mg; yield, 70%) as a pale pink oily substance.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH2:22][CH2:23][CH3:24].C(O)(=O)C(O)=O>C(#N)C>[CH2:21]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 51. Enantiomer E1 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.15 g, 0.77 mmol), acetonitrile (6 mL), potassium carbonate (0.21 g, 1.55 mmol), n-butylbromid, (0.08 mL, 0.77). Flash chromatography on silica gel (Ethyl acetate/methanol, 7:1). Yield: 0.085 g. [α]D=+24.8°; The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether; M.p. 157-158° C.; MS m/z (relative intensity, 70 eV) 255 (M+, 7), 212 (bp), 98 (52), 57 (40), 182 (37), 127 (16).
Reaction SMILES: COC([C:5]1[C:6](=[O:28])[NH:7][C:8]2[C:13]([C:14]=1[NH:15][CH:16]1[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18][CH2:17]1)=[CH:12][C:11]([Cl:27])=[CH:10][CH:9]=2)=O.C(O)(=O)C>Br>[Cl:27][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:28])[CH:5]=[C:14]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)N1CCC(Nc2c(C(=O)OC)c(=O)[nH]c3ccc(Cl)cc23)CC1
Agent: Br
Solvent: CC(=O)O
Product: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2[nH]1
Yield: 68.1 %

Procedure:
6-Chloro-4-(1-ethoxycarbonyl-piperidin-4-ylamino)2-oxo-1,2-dihydro-quinoline-3-carboxylic acid methyl ester (235 mg) was dissolved in HBr and acetic acid (1 mL, 30% by weight) and heated at 90° C. for 1 hr. The solvent was then evaporated to afford an orange solid (109 mg, 53%) which was carried onto the next step without characterization.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([S:36]([N:18]2[CH2:17][CH2:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH:14]=3)[CH2:19]2)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CCNC2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCc2cc(OCCCN3CCCCC3)ccc2C1

Procedure:
2-Benzenesulfonyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (330 mg, 0.95 mmol), NEt3 (0.48 mL, 3.5 mmol), and benzenesulfonyl chloride (0.15 mL, 1.17 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product as a white solid (250 mg, 63% yld). MS(ES+) 415.3(M+H)+.
Reaction SMILES: C([O:3][C:4]([CH2:18][Cl:19])([CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:19][CH2:18][C:4]([CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1)[OH:3]
Reactant: O=COC(CCl)(CC(Cl)(Cl)Cl)c1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: OC(CCl)(CC(Cl)(Cl)Cl)c1cc(Cl)cc(Cl)c1

Procedure:
34.5 Grams of the product of Example 2 was mixed with 0.5 grams of p-toluenesulfonic acid and 400 ml. of methanol. The resulting mixture was heated under reflux conditions for a period of about 19 hours. Following the reaction period, the reaction mixture was cooled and excess methanol removed by rotary evaporation. The residual oil thus obtained was mixed with 400 ml. of methylene chloride and the resulting solution washed with 400 ml. of a 10% Na2CO3 solution and three-400 ml. portions of water. The organic layer was separated from the resulting mixture, dried over sodium sulfate and the methylene chloride removed by rotary evaporation. The white solid thus obtained was recrystallized from hexane. As a result of such operations, the desired α-(chloromethyl)-3,5-dichloro-α-(2,2,2-trichloroethyl)benzenemethanol product was obtained as a white crystalline solid having a melting point of 69°-70.5° C.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[CH:6][O:7][CH:8]=1)([CH3:3])[CH3:2].[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26](Br)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]>>[CH2:9]([O:11][C:12](=[O:33])[N:13]([C:22]1[CH:27]=[C:26]([C:6]2[O:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[N:25]=[C:24]([NH2:29])[C:23]=1[N+:30]([O-:32])=[O:31])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10]
Reactant: CC(C)c1cocn1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(C(C)C)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-isopropyl-oxazole (54 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (71 mg) as a yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: COC(=O)Cc1ccccc1N
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1NCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title B compound, (2-amino-phenyl) acetic acid methyl ester (4.2 g, 25.4 mmol) is dissolved in DMF (30 mL). Powdered potassium carbonate (8.78 g, 63.5 mmol) and t-butyl bromoacetate (4.12 mL, 27.9 mmol) are added and the reaction is stirred at room temperature for 18 h and then at 50° C. for 1 h. The reaction is diluted with water (300 mL) and extracted with EtOAc (2×200 mL). Combined EtOAc layers are washed with water (2×100 mL) then brine (100 mL), dried over anhydrous MgSO4, filtered and concentrated to give a viscous brown oil. This residue is chromatographed on a 110 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 10:90 (EtOAc:hexane) to 25:75 over 30 min. Fractions containing product are combined and evaporated to yield [2-(t-butoxy-carbonylmethyl-amino)-phenyl]-acetic acid methyl ester as a clear amber oil: [M+1]+=280.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:40][C:41]1[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=1[NH2:43]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[F:40])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Nc1ccccc1F
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4ccccc4F)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (8 mL) was added 2-fluoroaniline (68.4 mg, 0.615 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (191 mg) as a yellow solid. LC-MS (ES) m/z=435 [M+H]+.
Reaction SMILES: [Br-].[Li+].[C:3]([Li])([CH3:6])([CH3:5])[CH3:4].[Cl:8][C:9]1[CH:22]=[CH:21][C:20]2[CH:19]3[CH2:23][C:12]([CH2:24][N:25]4[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]4)([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=1>O1CCCC1>[Cl:8][C:9]1[CH:22]=[CH:21][C:20]2[CH:19]3[CH2:23][C:12]([CH2:24][N:25]4[CH2:26][CH2:27][C:28]([C:3]([CH3:6])([CH3:5])[CH3:4])([OH:31])[CH2:29][CH2:30]4)([C:13]4[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]=2[CH:10]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: [Li]C(C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C1(O)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Temperature: 25 °C
Yield: 52 %

Procedure:
To a cooled solution (-78° C.) of lithium bromide (770 mg, 8.87 mmol, 1.5 eq) in tetrahydrofuran (60 mL) under nitrogen was added recently titrated t-butyllithium (1.7M in pentane, 4.20 mL, 7.10 mmol, 1.2 eq). The resulting strong yellow color was quenched on the addition of a 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 1m) (2.00 g, 5.92 mmol) solution in tetrahydrofuran (15 mL). The reaction was warmed to room temperature over 10 min and quenched with water (50 mL). The aqueous phase was extracted with ethyl acetate (3×60 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction mixture was purified by flash chromatography over silica gel (150 mL, eluent: 15% ethyl acetate in hexane) to obtain 1.22 g (52%) of the title compound as a white solid. TLC analysis (Rf 0.23, 20% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 7.24 (m, 1H), 7.14 (m, 2H), 6.95 (m, 3H), 6.87 (m, 1H), 4.24 (br s, 1H), 3.56 (s, 2H), 2.82 (m, 2H), 2.59 (d, J=1.4 Hz, 2H), 2.50 (m, 2H), 1.74 (m, 2H), 1.50 (m, 2H), 0.91 (br s, 9H) MS (CI, CH4) m/z 396 (M+1,100), 398 (35), 424 (M+29,17), 378 (45), 360 (6). The free base was dissolved in diethyl ether containing a small amount of methylene chloride and acidified with ethereal HCl. The hydrochloride salt was filtered, washed with fresh ether and dried in vacuo (60° C., 13 pascal, 18 h) to yield a white solid, mp 294°-296° C.
Reaction SMILES: C1COCC1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([O:38][C:39](=[O:48])[NH:40][CH2:41][CH:42]=[CH:43][Si](C)(C)C)([CH3:37])([CH3:36])[CH3:35].I[C:50]1[CH:68]=[CH:67][C:53]([O:54][CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[C:58]([CH3:66])[CH:57]=2)=[CH:52][CH:51]=1>C1C=CC=CC=1.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:34]([O:38][C:39](=[O:48])[NH:40][CH2:41][C:42]([C:50]1[CH:68]=[CH:67][C:53]([O:54][CH2:55][C:56]2[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[N:59]=[C:58]([CH3:66])[CH:57]=2)=[CH:52][CH:51]=1)=[CH2:43])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCC=C[Si](C)(C)C
Reactant: Cc1cc(COc2ccc(I)cc2)c2ccccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=C(CNC(=O)OC(C)(C)C)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 50 °C
Yield: 14.7 %

Procedure:
THF (1.5 mL), Pd(OAc)2 (20 mg, 0.089 mmol, 8% eq) and 1,2-bis(diphenylphosphino)ethane (35.5 mg, 16% eq) were mixed under N2, degassed and stirred to give orange yellow mixture. A premixed solution of (3-trimethylsilanylallyl)-carbamic acid tert-butyl ester (250 mg, 1.09 mmol) from (7b) and 4-(4-iodo-phenoxymethyl)-2-methyl-quinoline (410 mg, 1.0 eq) from (7c) in benzene (3 ml) was added. The resulting mixture was heated at 50° C. over the weekend, then cooled to rt, diluted with ether, washed with water, dried and concentrated. {2-[4-(2-Methyl-quinolin-4-ylmethoxy)-phenyl]-allyl}-carbamic acid tert-butyl ester (65 mg, 14.8%) was obtained after the crude was purified by flash column chromatography (20%–40% ethyl acetate-hexanes). MS Found: (M+H)+=405.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:14]([C:3]1[C:2]2[O:1][CH2:19][CH2:18][O:13][C:12]=2[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:16])=[O:15]
Reactant: CCOC(=O)c1ccc(O)c(O)c1[N+](=O)[O-]
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1[N+](=O)[O-])OCCO2
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A mixture of ethyl 3,4-dihydroxy-2-nitrobenzoate (4.97 g, 21.9 mmol), 1,2-dibromoethane (6.70 g, 43.8 mmol), and potassium carbonate (6.04 g, 43.8 mmol) in DMF (100 mL) was stirred at 80° C. overnight. To the reaction mixture was added ice/water (100 mL), and the resulting mixture was extracted with EtOAc (200 mL×2). The extracts were combined and dried, and the solvent removed. The product was purified by silica gel column (10% v/v EtOAc in PE) to give ethyl 5-nitro-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (4.30 g, 78% yield). ESI MS: m/z 254 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[C:49]([OH:51])=[O:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:53].O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[S:40][C:41]([C:44]4[O:45][CH:46]=[CH:47][CH:48]=4)=[CH:42][N:43]=3)[CH:32]=2)[O:11][C@@H:10]1[C:49]([O:51][CH3:53])=[O:50])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.4 %

Procedure:
To the solution of acid 104 (1.7 g, 2.35 mmol) in CH2Cl2 (7.8 mL) was added TMSCHN2 (1.4 mL, 2.82 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. H2O was added to the reaction mixture and then extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided the desired methyl ester 105 (560 mg, 32%) as a solid. MH+737.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CCO>[OH:14][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A suspension of 7-nitro-1-tetralone (2.00 g, 10.5 mmol) in EtOH (15 mL) was cooled by an ice water bath and treated with NaBH4 (0.40 g, 10.6 mmol). The mixture was stirred at room temperature for 2 h and then poured into ice water (50 mL) and extracted with EtOAc (3×20 mL). The extract was washed with NaCl solution, dried (MgSO4), filtered and concentrated to give a white solid (1.92 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]([NH2:10])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30](O)(=[O:41])[CH2:31][NH:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34].C1C=C(SSC2N=CC=CC=2)N=CC=1>C(Cl)Cl>[CH3:1][C:2]([NH:10][C:30](=[O:41])[CH2:31][NH:32][C:33](=[O:34])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: CC(C)(N)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: CC(C)(NC(=O)CNC(=O)c1ccccc1)c1ccccc1
Yield: 89.9 %

Procedure:
1.0 g of α,α-dimethylbenzylamine and 1.95 g of triphenylphosphine were dissolved in 100 ml of anhydrous methylene chloride. 1.33 g of hippuric acid and 1.63 g of 2,2'-dipyridyl disulfide were added in that order to the solution, and the mixture was heated under reflux for 2 hours. At the end of this time, the reaction solution was washed with a 10% w/v aqueous solution of sodium hydroxide and then with 1N aqueous hydrochloric acid, and dried over anhydrous sodium sulfate After concentration of the reaction solution by evaporation under reduced pressure, the resulting residue was subjected to silica gel column chromatography for separation and purification (using as eluent a 1:1 by volume mixture of hexane and ethyl acetate), to give 1.97 g (yield 90%) of the title product melting at 156°-157° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[F:30])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Si:31]([O:38][CH2:39][CH2:40][CH2:41][CH2:42]I)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O.C(COC)OC>[Si:31]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH:22]([C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30])[S:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an argon gas stream and at −78° C., n-butyl lithium (a 1.57M hexane solution, 0.701 ml, 1.10 mmol) was added to a dimethoxyethane (5 ml) solution of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (303 mg, 1.00 mmol) obtained in Example 5. The mixture was stirred at −78° C. for 1 hour and then, at room temperature for 30 minutes. The reaction mixture was cooled to −78° C., followed by the dropwise addition of 4-(t-butyldimethylsilyloxy)-1-iodobutane (0.260 ml, 1.00 mmol). While elevating the temperature of the reaction mixture to room temperature, stirring was conducted for 15 hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water and brine, dried over MgSO4, and concentrated. The residue thus obtained was purified by medium-pressure chromatography on a silica gel column (8% ethyl acetate-hexane), whereby the title compound (401 mg, 82%) was obtained as a colorless solid. The resulting solid was recrystallized from hexane to yield colorless needle crystals.
Reaction SMILES: [OH-].[Li+].[CH2:3]([NH:5][C:6](=[O:27])[NH:7][C:8]1[CH:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][N:9]=1)[CH3:4].Cl>O.CCO>[CH2:3]([NH:5][C:6](=[O:27])[NH:7][C:8]1[CH:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1)[CH3:4]
Reactant: CCNC(=O)Nc1cc(NCc2cccnc2)c(C(=O)OCC)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNC(=O)Nc1cc(NCc2cccnc2)c(C(=O)O)cn1
Temperature: 60 °C
Yield: 95.2 %

Procedure:
Lithium hydroxide (0.310 g, 7.29 mmol) dissolved in water (2 mL) was added to a solution of iv (0.250 g, 0.730 mmol) in EtOH (2 mL) THF (5 mL). The mixture was warmed to 60° C. for 3 h, cooled to room temperature and reduced in vacuo. The resulting residue was re-dissolved in water (2 mL) and the pH adjusted to pH 2-3 using conc. HCl (35%). The resulting colourless precipitate was filtered, washed with water and dried in vacuo to give vi (0.219 g, 0.695 mmol, 95%) as a colourless powder. 1H NMR (300 MHz, DMSO-d6): δ 9.10 (1H, s), 8.65-8.57 (2H, m), 8.07 (1H, br), 7.75 (1H, dt, J 8.2 and 1.5), 7.38 (1H, dd, J 7.7 and 4.6), 6.64 (1H, s), 4.45 (2H, d, J 6.1), 3.14 (2H, dq, J 7.2 and 5.6), 1.05 (3H, t, J 7.2); [M+H]+ m/z=316.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH:8]=[O:9].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9]
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a 0° C. solution of 3,5-dichloropyridine-4-carbaldehyde (7.0 g, 40 mmol) in anhydrous methanol (500 mL) was added sodium borohydride (2.3 g, 60 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (150 mL) was added and MeOH was evaporated. The mixture was extracted with ethyl acetate (2×100 mL) and 2-butanol (1×100 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (3,5-dichloropyridin-4-yl)methanol (6.4 g, 90% yield), which was used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[C:16]([NH:17]C(=O)OC(C)(C)C)=[CH:15][N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[B-](F)(F)(F)[F:34].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CN(C)C=O>[C:1]([NH:4][C:5]1[CH:32]=[CH:31][C:8]([C:9]([NH:11][C:12]2[C:16]([NH2:17])=[C:15]([F:34])[N:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=2)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(=O)Nc1ccc(C(=O)Nc2nn(-c3ccccc3)cc2NC(=O)OC(C)(C)C)cc1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Nc2nn(-c3ccccc3)c(F)c2N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3-{[4-(acetylamino)benzoyl]amino}-1-phenyl-1H-pyrazol-4-yl)carbamate (15 mg, 0.034 mmol) in methylene chloride (1 mL) and dimethylformamide (1 mL) was added selectfluor (24 mg, 0.069 mmol) and the resulting solution was stirred overnight at rt. The reaction was evaporated to dryness and purified by reverse phase LC to give the desired product as white solid. ESIMS calcd 454.18 (M++H), found 454.2 (M++H).