Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].[OH-].[K+].I[CH2:15][CH3:16]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][CH2:15][CH3:16])[CH:5]=[O:6]
Reactant: O=Cc1cc(F)c(O)c(Cl)c1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(F)cc(C=O)cc1Cl
Yield: 98 %

Procedure:
3-Chloro-5-fluoro-4-hydroxybenzaldehyde (1.0 gram, 5.7 mmol) in THF (40 mL) was heated at reflux for 17 hours with KOH (534 mg, 9.5 mmol, 1.7 eq) in water (5 mL) and iodoethane (1 mL, 2.2 eq). The reaction was then transferred to a separatory funnel with water and extracted with methylene chloride (thrice, 150 mL each). The combined organic layers were washed with 10% aqueous HCl (40 mL), dried (MgSO4), and concentrated to a viscous orange liquid to yield 1.13 g of 3-chloro-4-ethoxy-5-fluorobenzaldehyde (98%). 1H-NMR (500 MHz, CDCl3): 9.84 (d, J=1.9 Hz, 1H), 7.71 (t, J=1.6 Hz, 1H), 7.53 (dd, J=1.9, 10.7 Hz, 1H), 4.37-4.32 (m, 2H), 1.47-1.40 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][NH:13]1)=[O:11].[C:21](OC(C)(C)C)(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>C(N(CC)CC)C>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][N:13]1[C:21](=[O:26])[CH2:22][C:23](=[O:24])[CH3:25])=[O:11]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-methanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetate was reacted with tert-butyl acetoacetate in the presence of triethylamine to give the title compound. MS (ESI): m/z=292.2 [M+H]+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15]O)[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:50]I>C(#N)C.CCOCC>[I:50][CH2:15][CH2:14][C@H:13]1[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10][C@@H:9]1[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCO)O2)c(=O)[nH]c1=O
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCI)O2)c(=O)[nH]c1=O
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution of 3'-O-t-butyldimethylsilyl-5'-deoxy-5'-hydroxymethyl thymidine prepared according to the method of Example 5 (0.3 g, 0.9 mmol) in dry acetonitrile (5 ml) and ether (3.4 ml) were added 3 eq of triphenyl phosphine (0.7 g, 2.8 mmol), 4 eq of imidazole (0.3 g, 3.7 mmol) and 2.2 eq of iodine (0.5 g, 2.8 mmol). The reaction mixture was stirred for 45 min and the solvent was evaporated. Ethyl acetate was added to the residue and the residue washed with water, saturated sodium chloride and dried with sodium sulfate. The title compound was purified by flash chromatography using a 30-50% gradient of ethyl acetate in hexane. The yield was 90%.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:16])(=[O:15])[CH:7]2[CH:8]3[CH2:13][CH2:12][CH:11]([CH:6]2[C:5](=[O:14])[NH:4]1)[CH:10]=[CH:9]3.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CN(C)C=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][N:4]1[C:5](=[O:14])[CH:6]2[CH:11]3[CH2:12][CH2:13][CH:8]([CH:7]2[S:3]1(=[O:15])=[O:16])[CH:9]=[CH:10]3
Reactant: O=C1NS(=O)(=O)C2C3C=CC(CC3)C12
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2C3C=CC(CC3)C2S(=O)(=O)N1CCCCBr
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 15.9 %

Procedure:
A solution of 456 mg (19 mmol) of sodium hydride (prepared from 760 mg of 60% sodium hydride in mineral oil by pentane wash) in 40 ml of dimethylformamide is treated portionwise with 4.05 g (19 mmol) of 3a,4,7,7a-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide at 0° C. The resulting solution is added dropwise to a solution of 12.3 g (57 mmol) of 1,4-dibromobutane in 40 ml of dimethylformamide. The mixture is maintained with stirring at room temperature for 22.5 hours. The solvent is removed under high vacuum and the residue partitioned between methylene chloride and water. The combined methylene chloride extracts are washed with brine and dried over MgSO4. Filtration and removal of solvent in vacuo gives an oily solid which is triturated with ethyl ether and filtered to give 1.05 g of the title compound, mp 118°-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C>[Pd].C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1cc(N2CCN(C(=O)c3ccccc3)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A suspension of (4-(3-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (2.0 g, 9.0 mmol), 5 ml acetic acid and palladium on carbon (100 mg, 5%) in 50 ml ethanol was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered with the aid of celite. Crude (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (1.2 g, 41%) was obtained after removing of solvents. A suspension of (4-(3,4-diaminophenyl)piperazin-1-yl)(phenyl)methanone (0.2 g, 0.67 mmol), acetic acid (0.23 ml, 4.0 mmol) and 40% oxalaldehyde (0.14 ml, 1.0 mmol) in 40 ml acetonitrile was stirred at 50° C. under argon atmosphere overnight. The reaction was quenched with the 5 ml water and extracted with ethyl acetate (3×40 ml). The extraction was concentrated after drying over anhydrous sodium sulfate. Phenyl(4-(quinoxalin-6-yl)piperazin-1-yl)methanone (0.060 g, 28%) was obtained by flash column chromatograph (10% acetone in ethyl acetate). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.37 (d, br, 4H), 3.69 (s, br, 2H), 4.01 (s, br, 2H), 7.30 (d, J=2.7 Hz, 1H), 7.48 (m, 5H), 7.50 (dd, J=9.3, 2.7 Hz, 1H), 7.56 (d, J=9.3 Hz, 1H), 8.65 (d, J=1.9 Hz, 1H), 8.73 (d, J=1.9 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 49.1, 49.3, 110.8, 123.0, 127.6, 29.0, 130.4, 130.5, 1135.7, 139.0, 142.6, 144.9, 151.9, 145.6, 170.9.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[C:9](=[O:23])[O:10][C:11]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:12]=2[C:13]=1[CH3:14])(=O)=O.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(C)C.CC(OC)(C)C>[CH3:22][O:21][C:15]1[C:12]2[C:13]([CH3:14])=[C:8]([CH2:7][CH2:6][N:33]3[CH2:34][CH2:35][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:31][CH2:32]3)[C:9](=[O:23])[O:10][C:11]=2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1
Reactant: COc1cc(OC)c2c(C)c(CCOS(C)(=O)=O)c(=O)oc2c1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4ccccc4)CC3)c(=O)oc2c1
Yield: 50 %

Procedure:
Process B; starting materials: 3-[2-(methanesulphonyloxy)ethyl]-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 35) and 1-phenylpiperazine; yield 50%; m.p. 112°-114° C. (from isopropanol/TBME).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][NH:22][CH:23]2[CH3:28])(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[CH:27][C:18]=4[S:15]([CH3:14])(=[O:16])=[O:17])[CH:23]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1cccc2S(C)(=O)=O
Product: CC1c2cccc(S(C)(=O)=O)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:34]2[CH:39]=[N:38][CH:37]=[CH:36][N:35]=2)[CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(-c3cnccn3)c2)c1N
Temperature: 160 °C
Yield: 5.2 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-iodo-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (130 mg, 0.27 mmol) and 2-tributylstannylpyrazine (119 mg, 0.32 mmol) in DMF (2 mL) was added tetrakis(triphenylphosphine) palladium (catalytic) and the mixture was heated in microwave at 160° C. for 15 min. The solvent was removed and the residue was dissolved in EtOAc. The organics were washed by water, brine and concentrated. The crude material was purified by preparatory HPLC to provide the desired product as beige solid (6.2 mg, 5%). HPLC (4 minute 10-90 gradient) tR 2.12 min; MS m/z 439.19 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:22]2[C:9](=[CH:10][C:11]3[CH:12]=[C:13]4[C:18](=[C:19]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:20]=3[CH:21]=2)[CH:17]=[CH:16][CH:15]=[CH:14]4)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][C:12]1[C:11]2[CH:10]=[C:9]3[C:8]4[C:3]([C:2]([CH3:29])([CH3:1])[C:22]3=[CH:21][C:20]=2[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[CH:17]2)=[CH:4][CH:5]=[CH:6][CH:7]=4
Reactant: CC1(C)c2ccccc2-c2cc3cc4ccccc4c(-c4ccccc4)c3cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)c2ccccc2-c2cc3c(Br)c4ccccc4c(-c4ccccc4)c3cc21
Temperature: 60 °C
Yield: 68.1 %

Procedure:
13,13-dimethyl-11-phenyl-13H-indeno[1,2-b]anthracene (6.3 g, 0.017 mol) and N-bromosuccinimide (3.76 g, 0.017 mol) were dissolved in carbon tetrachloride (150 ml), and the reaction mixture was stirred under reflux for 4 hours at 60° C. After the reaction was terminated, the reaction solution was extracted with distilled water, and purified by column chromatography to give 6-bromo-13,13-dimethyl-11-phenyl-13H-indeno[1,2-b]anthracene (5.2 g, yield=68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][OH:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:20]>>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([C:15]([OH:20])=[O:16])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: O=c1cc(CO)occ1OCc1ccccc1
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (93.4 g, 401 mmol) in 2.6 L of acetone was added 400 mL of Jone's reagent (2.45 M) at 0° C. The reaction was warmed to room temperature, and the mixture was stirred overnight. The solid was removed by filtration, and the filtrate was concentrated. The concentrated residue was poured into water. The resulting white solid was collected and washed with water and dried to obtain 5-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid. 1H NMR<5 (400 MHz, d6-DMSO): 8.34 (s, 1H), 7.42-7.33 (m, 5H), 6.91 (s, 1H), 4.95 (s, 2H).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH2:10][O:11][C:12](/[C:14](/[C:22]#[N:23])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C(O)C>[NH2:23][C:22]1[O:7][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]=1[C:12]([O:11][CH2:10][CH3:9])=[O:13]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1
Solvent: CCO
Product: CCOC(=O)C1=C(N)OC2=C(C(=O)CCC2)C1c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 1,3-cyclohexane dione (0.56 g, 5.0 mmole) in hot ethanol (10 ml) was added ethyl trans-a-cyanocinnamate (1.0 g, 5.0 mmole) and the mixture heated at reflux for 18 h. The mixture was cooled to room temperature, filtered and washed with ethanol to provide the desired product (1.30 g, 83%) as a white powder. 1H NMR (400 MHz; CDCl3) d 7.29-7.0 (m, 5H); 6.2 (bs, 2H); 4.72 (s, 1H); 4.09-3.96 (m, 2H); 2.64-2.48 (m, 2H); 2.40-2.26 (m, 2H); 2.06-1.88 (m, 2H); 1.14 (t, 3H, J=7.4 Hz). LC MS shows MH+ at 314.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl>C(Cl)Cl>[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([O:4][CH2:3][CH:2]([F:5])[F:1])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(F)F
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of compound 2,2-difluoroethanol (1 g, 12.2 mmol) in CH2Cl2 (15 mL) was added TsCl (3.5 g, 18.3 mmol) at 0° C. The mixture was stirred at room temperature overnight. Then aqueous HCl was added to the mixture to adjusted the mixture to pH<7 and the mixture was separated. The aqueous phase was extracted with EtOAc and the combined organic phases was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=15:1) to provide 2,2-difluoroethyl 4-methylbenzenesulfonate. (2.5 g, yield: 86.8%). 1H-NMR (CDCl3, 400 MHz) δ 7.78 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.75˜6.04 (m, 1H), 4.10˜4.18 (m, 2H), 2.44 (s, 3H). MS (M+H)+: 267.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:28][C@H:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)[CH3:30]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C@H:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1)[CH3:30])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CCC(Oc3cccc(C(F)(F)F)c3)C2)cc1
Yield: 38.3 %

Procedure:
The title compound (D192) (64 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinic acid (D137) (120 mg, 0.305 mmol) and (S)-methyl 4-(1-aminoethyl)benzoate (D3) (65.7 mg, 0.305 mmol)
Reaction SMILES: [CH3:1]S(N)(=O)=O.[NH:6]1[CH2:10][CH2:9][N:8]=[C:7]1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17](N)=[CH:18][CH:19]=2)[C:14]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:13]1.CS(Cl)(=O)=O>N1C=CC=CC=1>[NH:6]1[CH2:10][CH2:9][N:8]=[C:7]1[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:1])[C:14]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:13]1
Reactant: CS(N)(=O)=O
Reactant: CS(=O)(=O)c1cn(CC2=NCCN2)c2ccc(N)cc12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cccc2c(S(C)(=O)=O)cn(CC3=NCCN3)c12

Procedure:
N-1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indol-5-yl]-methanesulfonamide, mp 232-233° C., was prepared from 1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indol-5-ylamine by treatment with methane sulfonylchloride and pyridine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:24])[O:4]1.CC(C)([O-])C.[K+].Cl[C:39]1[N:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41]([OH:43])=[O:42]>CN(C=O)C>[CH3:12][C:9]1([CH3:11])[O:10][CH:6]2[CH:5]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[O:4][CH:3]([CH2:2][O:1][C:39]3[N:47]=[CH:46][CH:45]=[CH:44][C:40]=3[C:41]([OH:43])=[O:42])[CH:7]2[O:8]1
Reactant: CC1(C)OC2C(CO)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Reactant: O=C(O)c1cccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC2C(COc3ncccc3C(=O)O)OC(n3cnc4c(NC(=O)Nc5ccccc5)ncnc43)C2O1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
To a stirred solution of 1-[9-(6-hydroxymethyl-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl]-3-phenyl-urea (43 mg, 0.1 mmol) in dry N,N′-dimethylformamide (1 mL) at 23° C. was added potassium tert-butoxide (45 mg, 0.4 mmol). After 30 min, 2-chloronicotinic acid (60 mg, 0.4 mmol) was added to the solution. The resulting mixture was stirred at 23° C. for 15 h and then quenched with water (1 mL), suspended in ethyl acetate (50 mL), washed with brine (3×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. Preparative reverse-phase HPLC was used to obtain the pure compound (15 mg, 27% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.15 (s, 1H), 9.16 (s, 1H), 8.65 (s, 1H), 8.05 (dd, J=8.5 Hz, 3.5 Hz, 1H), 7.94 (dd, J=9.0 Hz, 3.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.32 (t, J=12.5 Hz, 2H), 7.05 (t, J=12.5 Hz, 1H), 6.96 (dd, J=12.5 Hz, 8.5 Hz, 1H), 6.25 (d, J=6.0 Hz, 1H), 5.80 (t, J=7.5 Hz, 1H), 5.10 (dd, J=9.0 Hz, 2.5 Hz, 1H), 4.67 (m, 1H), 4.53 (dd, J=20.0 Hz, 4.0 Hz, 1H), 4.36 (dd, J=20.0 Hz, 4.0 Hz, 1H), 1.59 (s, 3H), 1.38 (s, 3H). MW calculated for C26H25N7O7 (MH+) 548. found 548 by LCMS.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([F:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([OH:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([O:25][C:13]2[CH:14]=[CH:15][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[F:17])[CH:24]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 24 step (i) and the product of example 18 step (iv).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: CC(C)(C)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 3,3-dimethylbutylamine (0.278 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.543 g, 63%): TOF MS ES+ 346.2 (M+H)+, HRMS calcd for C19H25N3O2F 346.1931 (M+H)+, found 346.1921, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 100% purity.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:26])([C@@H:21]([CH3:25])[C@@H:22]([OH:24])[CH3:23])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1>N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:26])([C@@H:21]([CH3:25])[C@@H:22]([O:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:23])[CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: C[C@H](O)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@H](OS(C)(=O)=O)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 2.5 h
Yield: 99.9 %

Procedure:
140 mg (1.22 mmole) of methanesulfonyl chloride were added at 0° C. to a solution of 213 mg (0.72 mmole) of (2R*,3S*,4S*)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-2,4-pentanediol [prepared as described in step (b) above] in 4 ml of pyridine, and the mixture was stirred for 2.5 hours. At the end of this time, the pyridine was removed by distillation under reduced pressure. The resulting residue was mixed with a dilute aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and freed from the solvent by evaporation under reduced pressure, to afford 270 mg of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](C=O)[C:5]([Cl:10])=[CH:4][N:3]=1.[CH:11](OC)([O:14][CH3:15])[O:12][CH3:13]>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: COC(OC)OC
Reactant: O=Cc1cc(Br)ncc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1cc(Br)ncc1Cl
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a sol. of 2-bromo-5-chloro-pyridine-4-carbaldehyde (43.9 g, 199 mmol) in MeOH (800 mL) were successively added at rt trimethyl orthoformate (65.3 mL, 597 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10.0 mmol). This reaction mixture was then heated to reflux for 3 h. The mixture was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and this mixture was washed with aq. 10% K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the title compound (51.7 g, 97%). LC-MS: tR=0.92 min; ES+: 309.06.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:27])[CH2:10][N:11]([CH3:26])[S:12]([C:15]2[C:16]3[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:17]=3[S:18][C:19]=2Br)(=[O:14])=[O:13])=[CH:5][CH:4]=1.Cl>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:27])[CH2:10][N:11]([CH3:26])[S:12]([C:15]2[C:16]3[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:17]=3[S:18][C:19]=2[NH2:1])(=[O:14])=[O:13])=[CH:5][CH:4]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(Br)sc2c1CCCC2=O
Reactant: N
Agent: Cl
Solvent: O
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1c(N)sc2c1CCCC2=O
Temperature: 110 °C

Procedure:
A concentrated aqueous ammonia (24 mL) was added to 2-bromo-7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonic acid[2-(4-fluorophenyl)-2-hydroxy-ethyl]-methyl-amide (210 mg). After heating at 110° C. for 4 hours, the reaction solution was poured into water, brought to pH 9 with 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate, the residue resulting from the removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (145 mg) was obtained as a colorless film.