Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([CH2:17][CH3:18])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:15]([C:13]2[C:12]([CH2:17][CH3:18])=[N:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH:14]=2)[OH:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOc1cccc(-n2cc(C=O)c(CC)n2)c1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C(O)C3CCCCC3)c(CC)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution (20 mL) of 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (2.2 g, 96%) as a pale-yellow oil.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=S)#[N:2].[NH2:13][C@@H:14]1[C:19]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=2[O:17][C:16]([CH3:27])([CH3:26])[C@H:15]1[OH:28].Cl.CN(C)CCCCCN=C=N>CN(C)C=O>[C:1]([N:3]=[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:13][C@@H:14]1[C:19]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=2[O:17][C:16]([CH3:26])([CH3:27])[C@H:15]1[OH:28])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: N#CNC(=S)Nc1ccccc1
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
To a solution of N-cyano-N'-phenylthiourea (2.11 g, 11.9 mmol) and (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.0 g, 9.1 mmol), title B compound, in dimethylformamide (20 mL) under argon was added 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (2.23 g, 11.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between 1N hydrochloric acid and ethyl acetate. The organic phase was separated and the aqueous phase was reextracted with ethyl acetate. The combined organic extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes (7:3) to give a colorless solid which was triturated with ether to yield the title compound (0.35 g), m.p. 215°-216° C.: [α]D25 =-33.5° (c=1, MeOH); 1H NMR (DMSO-d6) δ 9.28 (s, 1 H), 7.58 (d, J=8.0 Hz, 3 H), 7.35 (m, 4 H), 7.15 (m, 1 H), 6.90 (d, J=8.2 Hz, 1 H), 5.92 (br s, 1 H), 4.92 (t, J=9.0 Hz, 1 H), 3.72 (br d, J=5.9 Hz, 1 H), 1.41, 1.18 (s, 3 H each); 13C NMR (DMSO-d6) 159.2, 156.3, 137.5, 132.6, 132.5, 129.0 124.8, 124.7, 123.6, 119.0, 117.8, 117.0, 102.6, 80.4, 70.9, 51.9, 26.6, 18.6; IR (KBr) 2226, 2179, 1609, 1582, 1491, 1267 cm-1.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[CH:55][C:54]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:52]=[CH:53][C:54]([C:57]2[CH:58]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:60]=[CH:61][CH:62]=2)=[CH:55][N:56]=1
Reactant: COc1ncc(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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: CN(C)C=O
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cn1
Temperature: 25 °C
Yield: 19.8 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2-methoxy-pyrimidin-5-yl)-phenylamine (0.013 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.005 g of product in 20% yield: LCMS (ESI) m/z 390 (MH+).
Reaction SMILES: [CH3:1][C@:2]12[CH2:20][CH2:19][C@H:18]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@:15]3([CH:16]=[O:17])[CH2:14][CH2:13][C:12](=[O:21])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][CH2:3]2.[CH2:22](OCC)C.CCCCCC>O1CCCC1>[CH3:22][C@@H:8]1[CH:9]=[C:10]2[C@:15]([CH:16]=[O:17])([CH2:14][CH2:13][C:12](=[O:21])[CH2:11]2)[C@@H:18]2[C@@H:7]1[C@H:6]1[C@@:2]([CH2:20][CH2:19]2)([CH3:1])[CH2:3][CH2:4][CH2:5]1
Reactant: CCOCC
Reactant: C[C@@]12CCC[C@H]1[C@@H]1C=CC3=CC(=O)CC[C@]3(C=O)[C@H]1CC2
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[C@@H]1C=C2CC(=O)CC[C@]2(C=O)[C@H]2CC[C@]3(C)CCC[C@H]3[C@H]12

Procedure:
The 7α-methyl-4-androstene-3,19-diones are produced by alkylating the corresponding 4,6-androstadiene-3,19-dione with dimethyllithium copper in an inert solvent such as diethyl ether, tetrahydrofuran, hexane or mixtures of these at temperatures ranging from -78° C. to 25° C. Tetrahydrofuran is the preferred solvent and temperatures between -5° C. to 10° C. provide optimum results. Quenching the initially formed enolate anion with a weak protonating agent such as a saturated solution of ammonium chloride, oxalic acid or boric acid provides the 7α-methyl-5-androstene-3,19-dione. Quenching the enolate with a strong protonating agent such as hydrochloric acid provides the 7α-methyl-4-androstene-3,19-diones.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10](O)[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([Cl:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(O)CC(C)C)oc2ccc(Cl)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(C(Cl)CC(C)C)oc2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution (10 mL) of 1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (650 mg) synthesized above in toluene was added thionyl chloride (225 μL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (668 mg, 96%) as a pale-yellow oil.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][CH:12]1[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([SH:23])[S:21][CH:22]=2)[CH2:14][N:13]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25].O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:27]([O:26][C:24]([N:13]1[CH:12]([CH3:11])[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([S:23][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:21][CH:22]=2)[CH2:14]1)=[O:25])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CC(c2csc(S)n2)=CCC1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCC(C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 1.24 ml, 1.24 mmol) was added at 0° C. to a solution of allyl 2-methyl-5-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (368 mg, 1.24 mmol) in THF (2.4 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 4.73 g, 2.5 mmol) and the solution was allowed to stand in a refrigerator for 13 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 4/1→3/1) to give allyl (4R,5S,6S)-3-[(4-(1-[(allyloxy)carbonyl]-6-methyl-1,2,5,6-tetrahydro-3-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (544 mg, 71%).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:20]([NH:27][C@H:11]1[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C@H:6]1[O:5][CH2:4][CH2:3][CH2:2][F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(OCCCF)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCCCF)C1
Yield: 86.6 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-(3-fluoropropoxy)-4-oxopiperidine-1-carboxylate obtained in Example (127b) (1.71 g, 6.21 mmol), benzylamine (0.75 g, 7 mmol), sodium (triacetoxy)borohydride (2.54 g, 12 mmol) and 1,2-dichloroethane (20 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 1.97 g of the title compound as a colorless oily substance (87%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([CH3:41])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([O:31]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>>[F:44][C:2]([F:43])([F:1])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([N:45]3[CH2:49][CH2:48][CH2:47][CH2:46]3)=[O:31])[CH2:18]2)[CH3:41])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C1CCNC1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 420 and using the compound obtained in Example 362 and pyrrolidine, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[CH2:94]([N:101]1[CH2:106][CH2:105][CH:104]([NH2:107])[CH2:103][CH2:102]1)[C:95]1[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=1>>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:94]([N:101]1[CH2:106][CH2:105][CH:104]([NH:107][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:3]=2)[CH2:103][CH2:102]1)[C:95]1[CH:96]=[CH:97][CH:98]=[CH:99][CH:100]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCN(Cc6ccccc6)CC5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol (Intermediate BA7) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoro-acetate (Example 46) replacing 1-(2-aminoethyl)piperidine with 1-benzyl-4-aminopiperidine. MS (ES+) m/e 700 (MH+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][N:20]=[C:19]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1.O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][N:20]=[C:19]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: Cc1cc2[nH]nc(-c3ccccc3)c2cc1N
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2[nH]nc(-c3ccccc3)c2cc1NS(=O)(=O)c1ccccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
2-Methylsulfonyl-N-(6-methyl-3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 0.45 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.4 g of 5-amino-6-methyl-3-phenyl-1H-indazole in 35 ml of pyridine. The reaction mixture is then stirred for 10 minutes at a temperature in the region of 0° C. then 16 hours at a temperature in the region of 20° C., and is then diluted with 50 ml of water. After settling out, the aqueous phase is extracted with 50 ml and then 25 ml of ethyl acetate. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a silica column (particle size 63-200 μm), eluting with a dichloromethane/methanol (99/1 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up and recrystallized from 20 ml of diethyl ether. The crystals are filtered off through sintered glass, washed with 2 times 10 ml of diisopropyl ether, partially dried and then dried under reduced pressure (3 kPa) at a temperature in the region of 50° C. 0.27 g of 2-methylsulfonyl-N-(6-methyl-3-phenyl-1H-indazol-5-yl)benzenesulfonamide are obtained in the form of a beige powder melting at 239° C. (analysis C21H19N3O4S2 % calculated C, 57.13; H, 4.34; N, 9.52; O, 14.49; S, 14.52. % found C, 56.66; H, 4.52; N, 9.41; S, 14.15).
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:8][CH3:9])[C:3](OCC)=[O:4].[BH4-].[Na+]>O.C(O)C>[NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH2:8][CH3:9])[CH2:3][OH:4]
Reactant: CCOC(=O)C(N)(CC)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCC(N)(CO)c1ccccc1
Yield: 89.8 %

Procedure:
A solution of ethyl 2-amino-2-phenylbutanoate (0.162 g, 0.782 mmol) in 1:3 v/v water/ethanol (4 mL) was reacted with sodium borohydride (0.151 g, 3.908 mmol) at reflux for four hours. The reaction was concentrated and partition between water (5 mL), ethyl ether (10 mL) and 1N aqueous sodium hydroxide (0.39 mL). Solid sodium chloride was added to saturate the aqueous and separate the phases. The aqueous phase was separated and re-extracted with ethyl ether (2×20 mL). The combined ethereal extracts were washed with brine (25 mL), dried over potassium carbonate, filtered, and concentrated by rotary evaporation to afford the title compound as an oil (0.116 g, 0.702 mmol, 90%). 1H NMR (300 MHz, DMSO-D6) δ ppm 0.59 (t, J=7.54 Hz, 3 H) 1.49-1.80 (m, 4 H) 3.44 (d, J=5.15 Hz, 2 H) 4.63 (t, J=5.52 Hz, 1 H) 6.89-7.76 (m, 5 H). MS (DCI) m/z 166 (M+H)+.
Reaction SMILES: CN(C=O)C.[C:6]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:8][CH2:9][CH3:10])=[O:7].[CH:18]([S:20]([F:23])(=[O:22])=[O:21])=[CH2:19]>O>[C:6]([C:11]1[CH:12]=[CH:13][C:14]([NH:15][CH:19]=[CH:18][S:20]([F:23])(=[O:22])=[O:21])=[CH:16][CH:17]=1)([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CS(=O)(=O)F
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC=CS(=O)(=O)F)cc1
Temperature: 110 °C
Yield: 49.8 %

Procedure:
To a 75 mL DMF solution of 4-carboethoxyaniline (3.88 g, 23.5 mmol) was added ethenesulfonyl fluoride (3.3 mL, 30 mmol) under nitrogen. The solution was warmed to 100-120° C. for 6 hours. The cooled solution was slowly Poured into water and chilled in ice. The yellow solid precipitate was collected, dissolved in methylene chloride, washed with brine and dried (Na2SO4). After the solvent had been removed by distillation, the brown solid (5.4 g) was crystallized from methylene chloride/ether/hexane. The title compound (3.2 g, 49% yield) was obtained as a tan solid, mp 109.5°-111.5° C.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
Triethylamine (17.97 mL, 129.0 mmol) was added to a solution of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (24.8 g, 86.0 mmol) in dichloromethane (200 mL) at 0° C. Isobutylamine (9.40 mL, 94.6 mmol) was added dropwise to the mixture, and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was condensed under reduced pressure to a solid, which was triturated with water (200 mL). The precipitate was filtered, washed sequentially with water and hexanes, and dried to yield 27.5 g of 7-bromo-3-nitro[1,5]naphthyridin-4-yl-(2-methylpropyl)amine as a yellow powder, mp 114-115° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-:16].[Na+].[Na+].C([SiH](CC)CC)C.[C]=O>CN(C=O)C>[CH:15]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH3:9])=[CH:4][CH:3]=1)=[O:16]
Reactant: C[C@@H](NS(C)(=O)=O)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: CC[SiH](CC)CC
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NS(C)(=O)=O)c1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 15 h

Procedure:
Combine N-[(1R)-1-(4-bromophenyl)ethyl]-methanesulfonamide (10 g, 35 mmol), (1,1′-bis(diphenylphosphino)-ferrocene)palladium(II)chloride (733 mg, 0.9 mmol), sodium carbonate (3.81 g, 35 mmol) and DMF (50 mL) in a 300 mL PARR reactor. Add triethylsilane (11.6 mL, 0.72 mmol) and purge the reactor with carbon monoxide three times. Charge the reactor with carbon monoxide (50 psi); seal; and stir the mixture at 90° C. for 15 hours. Cool the reactor to ambient temperature; filter the resulting mixture over Celite® pad; and wash the pad with DCM (150 mL). Collect the filtrate and sequentially wash the filtrate with water then brine (2×80 mL). Concentrate the organic filtrate under reduced pressure to obtain the residue as an orange oil. Purify by silica gel flash chromatography eluting with hexane/EtOAc (0 to 30% EtOAc) to provide the title compound (5.6 g, 70%, ee>98%). MS (m/z): 228 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])/[C:24]#[N:25])=[C:19]([F:36])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:36])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C1C(C(=O)OC(C)(C)C)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Yield: 14 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1.1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile (1.28 g, 4 mmol) prepared in Example 85a, AgF (0.76 g, 6 mmol), and triethylamine (1.38 mL, 10 mmol) in dichloromethane (100 mL) at room temperature for 18 h to give rac-(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.3 g, 14%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:34]5[C:35]6[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:31]=[CH:32][CH:33]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cccc5ccccc45)ccc32)n1)c1ccccc1
Reaction time: 15 h

Procedure:
2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 271) (50 mg), 1-naphthyl boronic acid (22 mg), potassium carbonate (31 mg), and tetrakis(triphenylphosphine)palladium(0) (5 mg) were dissolved in degassed n-propanol (2.6 mL) and water (0.4 mL) and stirred at 80° C. under argon atmosphere. for 15 hours. Upon cooling, the reaction mixture was filtered through Celite® (the ppt was washed with 10 mL of EtOAc) and evaporated. The residue was purified by preparative thin layer chromatography eluted with 5% MeOH/CH2Cl2 giving 43 mg of the title compound. 1H NMR (500 MHz, CDCl3), δ 8.58 (br s, 1H), 8.40 (s, 1H), 7.96-7.90 (m, 4H), 7.59-7.27 (m, 10H), 6.85 (d, 1H, J=5.5 Hz), 6.45 (br s, 1H), 5.25 (s, 1H), 1.67 (d, 3H, J=7.0 Hz); Mass spectrum (ESI) 442.2 (M+1).