Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[C:26]([CH3:33])[CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]2[NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:32]2)=[C:26]([CH3:33])[CH:25]=1
Reactant: Cc1cc(F)ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc(F)ccc1N=C1N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Fluoro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-fluoro -2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-fluoro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: C1(CC([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[O:25])=[C:15]([CH:18]4[CH:22]([CH3:23])[CH2:21][CH2:20][O:19]4)[CH2:16][S:17][C@H:12]23)=O)C=CC=CC=1.CN1CCOCC1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>ClCCl.O>[NH2:10][C@@H:11]1[C:36](=[O:37])[N:13]2[C:14]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)=[O:25])=[C:15]([CH:18]3[CH:22]([CH3:23])[CH2:21][CH2:20][O:19]3)[CH2:16][S:17][C@H:12]12
Reactant: COc1ccc(COC(=O)C2=C(C3OCCC3C)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCOCC1
Product: COc1ccc(COC(=O)C2=C(C3OCCC3C)CS[C@@H]3[C@H](N)C(=O)N23)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
4-Methoxybenzyl (6R, 7R) -7-phenylacetamido-3-[(2RS,3SR)-3-methyltetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (0.692g) in dry dichloromethane (5ml) under argon was cooled to -20° C. This solution was then treated with 4-methylmorpholine (0.268g, 0.291ml) followed by a solution of phosphorus pentachloride in dichloromethane (0.415g in 10.37ml) in a rapid dropwise fashion. The solution was allowed to warm to -5° C. and maintained at this temperature for 0.5h. Methanol (5ml) was then added in one portion and the solution allowed to warm to room temperature, and stirred for 0.5h. Water (5ml) was then added and the solution rapidly stirred for a further 0.75h. The dichloromethane was evaporated at reduced pressure and replaced with ethyl acetate. The pH was adjusted to 7.5 with aqueous 880 ammonia. The aqueous phase was extracted with ethyl acetate and the combined organic layers washed with brine and dried. Removal of solvent and column chromatography on silica gel eluting with 60 and then 70% ethyl acetate in hexane afforded the (2S,3R) isomer of the title compound as a pale yellow foam, (0.197g, 37%); vmax (CH2Cl2) 1777, 1720 and 1613cm-1 ; δH (CDCl3) 0.89 (3H, d, J 7.2Hz), 1.56 (1H, m), 2.14 (1H, m), 2.73 (1H, m), 3.37 and 3.57 (2H, ABq, J 18.0Hz), 3.73 (1H, m), 3.82 (3H, s), 4.05 (1H, m), 4.79 (1H, d, J 4.8Hz), 4.93 (1H, d, 4.8Hz), 4.98 (1H, d, J 7.6Hz), 5.17 (2H, s), 6.88 (2H, d, J 8.6Hz) and 7.33 (2H, d, J 8.6Hz). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MH+ (405), MNa+ (427)].
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2[CH2:22][CH2:23][NH:24][CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH3:18])[CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:4]=2[O:3]1.[N:27]#[C:28]Br.C([O-])(=O)C.[Na+]>CO>[C:28]([N:24]1[CH2:25][C:20]2[C:5]3[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH3:18])[CH:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:4]=3[O:3][C:2]([CH3:1])([CH3:26])[C:21]=2[CH2:22][CH2:23]1)#[N:27]
Reactant: N#CBr
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(C#N)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A mixture of 4.6 g (0.0129 mole) of 5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1] benzopyrano[3,4-d]pyridine, 1.38 g (0.013 mole) of cyanogen bromide, 2.13 g (0.026 mole) of sodium acetate and 35 ml of methanol was stirred at 0° C for 3 hours, and then at ambient temperature for 12 hours. After removal of the solvent under reduced pressure, water was added to the residue and the mixture was extracted with diethyl ether. The organic layer was washed with 2 N HCl, followed by saturated NaCl solution. The ether layer was separated, dried over Na2SO4 and concentrated to give 2-cyano-5,5-dimethyl-8-(1,2-dimethylheptyl)-10-hydroxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine as a yellow oil (4.9 g, 99% yield) which crystallized upon standing.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:48][CH2:47][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[CH:39][C:38]2=[N:42][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:49])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:46])[O:23][C:24]2[CH:25]=[C:26]([F:45])[C:27]([F:44])=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:47][CH2:48]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)c(F)cc1-c1cccc-3c1
Yield: 59 %

Procedure:
Prepared in 59% yield from Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.10 (d, J=7.3 Hz, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.46-7.37 (m, 2H), 7.31 (d, J=7.7 Hz, 1H), 7.25 (s, 1H), 6.15-6.07 (m, 1H), 5.85-5.75 (m, 2H), 4.64 (br. s., 1H), 4.08-3.88 (m, 3H), 3.59 (t, J=11.4 Hz, 1H), 3.28 (br. s., 1H), 2.68-2.53 (m, 2H), 2.40 (s, 3H), 2.30-2.20 (m, 1H), 1.97-1.85 (m, 2H), 1.79-1.62 (m, 2H), 1.25 (s, 3H), 1.17 (s, 9H), 1.04 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 659.3.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[C:15]([NH:18][NH2:19])([NH2:17])=[NH:16].Cl.[OH-].[Na+]>ClCCl.CN(C)C=O>[C:15]([NH:18][NH:19][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)(=[NH:16])[NH2:17]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: N=C(N)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N=C(N)NNC(=O)c1ccc(Cl)nc1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 6-chloronicotinic acid (10.0 g) in dichloromethane (100 ml) was added dropwise dimethylformamide (10 ml) and thionyl chloride (5.1 ml), and the mixture was stirred for 1 hour with refluxing. The resulting reaction mixture was dropwise added to aminoguanidine hydrochloride (24.6 g) in a 2.2N aqueous sodium hydroxide solution (100 ml) under ice-cooling. After the dropwise addition, the mixture was stirred at said temperature for 10 minutes to give 6.87 g of a pale-brown solid by filtration (yield 51%).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][C:15]3([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=4)[CH2:19][CH2:20]3)[C:30](=[O:35])[CH2:31]2)(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
Triethylamine (400 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (440 mg) obtained in Reference Example 11 in dichloromethane (15 ml), 4-bromobenzenesulfonyl chloride (255 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. An aqueous sodium carbonate solution was added to the reaction solution, the material was extracted with dichloromethane, dried, concentrated, and purified by silica gel column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain the title compound (403 mg) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=1.O.C(=O)([O-])O.[Na+]>C(#N)C.CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: COc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: COc1ccc2nc(-c3ccc(O)cc3)cn2c1
Temperature: 90 °C
Yield: 81.6 %

Procedure:
2.15 g (corresponding to 10.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.25 g (corresponding to 10.0 mmol) of 2-amino-5-methoxypyridine were dissolved in 50 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 90° C. for 3.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The recovered precipitates were washed with acetonitrile, and dried under reduced pressure to obtain crude crystals. The resulting crude crystals were suspended in a mixed solution of 40 mL of water and 40 mL of methanol. The suspension was supplemented with about 20 mL of a saturated sodium hydrogencarbonate solution, and sonicated for 5 minutes by an ultrasonic washing machine. The precipitates were filtered and recovered from the resulting mixture, washed with water, and dried under reduced pressure, to obtain 1.96 g (corresponding to 8.16 mmol) of 2-(4′-hydroxyphenyl)-6-methoxyimidazo[1,2-a]pyridine (FIG. 1, Step 5).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][CH2:11][N:12]=1.C(O)(=O)C.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:9][CH2:10][CH2:11][NH:12]1
Reactant: Brc1ccccc1C1=NCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Brc1ccccc1C1CCCN1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
5-(2-Bromophenyl)-3,4-dihydro-2H-pyrrole (compound 8; 393 mmol, 88 g) was dissolved in methanol (1300 mL), then the acetic acid (330 mL) was added and the solution cooled to −65° C. under a nitrogen atmosphere. Sodium borohydride (589 mmol, 22.28 g) was added portionwise over 1 hour. The reaction was stirred at −65° C. for 30 minutes, then the cooling bath was removed and the reaction mixture temperature was allowed to rise to room temperature. The bulk of the methanol was removed under vacuum then 5N HCl (950 mL) was added and the solution extracted with ether (2×500 mL). The aqueous solution was then basified with sodium hydroxide pellets (310 g) with ice-bath cooling, maintaining the reaction temperature less than 30° C. The basified aqueous was then extracted with ethyl acetate (3×800 mL), the combined organics washed with brine (800 mL), dried with sodium sulfate, evaporated and chromatographed on 1 Kg of silica gel eluting with 19:1 to 9:1 methylene chloride-ethanol to give 2-(2-bromophenyl)pyrrolidine (68.5 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[Si:8]([O:15][CH2:16][CH2:17]Br)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>CN(C=O)C>[Si:8]([O:15][CH2:16][CH2:17][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1ccnc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To 86.4 mg (2.2 mmoles) of 61.1% sodium hydride mineral oil dispersion in 5 mL sieve dried DMF at 0° C. was added 136 mg (2.0 mmoles) of imidazole. The mixture was stirred at 0° C. under nitrogen for 15 minutes and 476 mg (2.0 mmoles) of neat t-butyldimethylsilyloxyethyl bromide was added. The ice-water bath was removed and the mixture stirred overnight and it was then partitioned between ether and ice-water. The organic phase was separated, washed thrice with ice-water, dried over sodium sulfate, filtered, and evaporated to give 282.3 mg (63%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=[O:13])=[C:7]2[N:17]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH3:18].[OH-].[Na+].CO>O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[C:7]2[N:17]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][C:30]#[C:31][CH3:32])=[CH:26][CH:27]=1)(=[O:20])=[O:21])[CH3:18]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C(=O)OCC)cnc3c(Br)cccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N(C)c2c(C(=O)O)cnc3c(Br)cccc23)cc1
Yield: 79.7 %

Procedure:
Ethyl 8-bromo-4-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-quinolinecarboxylate (0.52 g, 1.0 mmol), the product of Example 97, was treated with 1 N aqueous sodium hydroxide (1.1 mL) in 1:1 methanol:water (6 mL) to give 0.390 g of 8-bromo-4-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-quinolinecarboxylic acid as an off-white powder. Electrospray Mass Spec 489 and 490.9 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:10][S:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])[CH3:9])[CH:5]=[C:4]([F:17])[C:3]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20].[BH4-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([NH:10][S:11]([C:13]([CH3:16])([CH3:14])[CH3:15])=[O:12])[CH3:9])[CH:5]=[C:4]([F:17])[C:3]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(=NS(=O)C(C)(C)C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(NS(=O)C(C)(C)C)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Temperature: -48 °C
Reaction time: 10 h
Yield: 85.5 %

Procedure:
To a solution of N-(4-acetyl-2,6-difluoro-phenyl)-methanesulfonamide (1.84 g, 7.38 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (1.07 g, 8.86 mL) in THF (15 mL) was added dropwise Ti(OEt)4 (2.61 mL, 12.6 mmol) at room temperature. The mixture was stirred overnight at 90° C. The mixture cooled to room temperature and then was added brine. After the mixture was extracted three times with EtOAc, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by chromatography to yield N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 85%). To a solution of N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylimino)-ethyl]-phenyl}-methanesulfonamide (2.2 g, 6.24 mmol) in THF (20 mL) was added portionwise NaBH4 (944 mg, 24.9 mmol) dissolved in THF (2 mL) at −48° C. The mixture was stirred for 10 hours at −48° C. room temperature, and then CH3OH was added dropwise until gas was no longer evolved. The mixture was concentrated under reduced pressure, and then was purified by chromatography to afford N-{2,6-difluoro-4-[1-(2-methyl-propane-2-sulfinylamino)-ethyl]-phenyl}-methanesulfonamide (1.89 g, 50%).
Reaction SMILES: C1C2C(=CC(N)=CC=2)CC1.[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[NH:30][C:29](=[O:31])[C:28]3[C:27]4[CH2:32][CH2:33][CH2:34][C:26]=4[CH:25]=[CH:24][C:23]=3[N:22]=2)[CH:20]=1)=[O:15])[CH3:12]>>[CH2:11]([O:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:21]2[NH:30][C:29](=[O:31])[C:28]3[C:23](=[CH:24][C:25]4[CH2:32][CH2:33][CH2:34][C:26]=4[CH:27]=3)[N:22]=2)[CH:20]=1)=[O:15])[CH3:12]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCC4)c1
Agent: Nc1ccc2c(c1)CCC2
Product: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCC4)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 131, steps A-B, using indan-5-ylamine in step A. Step B yielded a 10:1 mixture of the titled compound and 1-(1-oxo-2,7,8,9-tetrahydro-1H-cyclopenta[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: C[O-]
Reactant: Cc1cc(Br)n2ccnc2c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)cc2nccn12
Yield: 62 %

Procedure:
A solution of 5-bromo-7-methylimidazo[1,2-a]pyridine (2 g, 0.01 mol) and sodium methoxide (25%, 10 mL) in methanol (10 mL) is heated under reflux for 48 h. The solvent is removed and the residue diluted with ethyl acetate (200 mL) and water (150 mL). The organic layer is separated and washed with water and brine, and dried over sodium sulfate. Evaporation of the solvent gave 5-methoxy-7-methylimidazo[1,2-a]pyridine (lg, 62%) as a white semi-solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Yield: 80.7 %

Procedure:
A stirred solution of 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268 A1) (0.21 g, 0.0008 mole) in a mixture of DME (10 ml) and water (30 ml) under argon was treated with 4-boronobenzoic acid (0.14 g, 0.0008 mole), sodium carbonate (0.39 g, 0.0037 mole) and tetrakis (triphenylphosphine)palladium (0) (16 mg), then heated under reflux for 4 hours. The mixture was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to leave the title compound as a white solid (0.19 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:31])=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCc1ccc(Br)cc1
Reaction time: 4 h
Yield: 39.9 %

Procedure:
Compound 41-2 (3.63 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (4.88 g) and N-bromosuccinimide (3.31 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature for 4 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.87 g) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2].[O:44]1CCN(C2C=CC(N)=CC=2)CC1>>[CH:1]([C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:6]([C:23]2[CH:30]=[CH:29][C:26]([C:27]([NH2:28])=[O:44])=[C:25]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[CH:34][CH:33]=3)[CH:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Nc3ccc(N4CCOCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: Nc1ccc(N2CCOCC2)cc1
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(Nc3ccc(N4CCOCC4)cc3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 11 %

Procedure:
According to Example 1(6), 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(4-morpholinophenylamino)benzonitrile was prepared using compound (6d) instead of compound (1e) and using 4-morpholinoaniline instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (33) (the second stage yield: 11%) was prepared as a white solid using 4-{3-isopropyl-4-(quinolin-3-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(4-morpholinophenylamino)benzonitrile instead of compound (1f).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:8]1[CH:31]=[C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:29]=[CH:28][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH:18](O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH3:7].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:28]=[CH:29][C:30]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:31][C:8]=2[CH2:5][CH2:6][CH3:7])[CH:16]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=S(Cl)Cl
Reactant: CCCc1cc(C2CCCCC2)ccc1OCCCOc1cccc(C(O)C(=O)OCC)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1cc(C2CCCCC2)ccc1OCCCOc1cccc(C(Cl)C(=O)OCC)c1
Reaction time: 6.5 h

Procedure:
Thionyl chloride (0.15 mL) was added to a solution of ethyl 4-(3-(2-propyl-4-cyclohexylphenoxy)propoxy)mandelate of Step C (0.71 g), pyridine (0.19 mL), and toluene (15 mL). The reaction mixture was stirred 6-7 h and then partitioned between ethyl acetate and water. The organic layer was washed twice with water, once with brine, dried over sodium sulfate, and filtered. The solvent was removed in vacuo and the resulting oil was used as such for the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(#N)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(CCO)cc1
Yield: 92.8 %

Procedure:
A mixture of 4-(2-hydroxyethyl)phenol (3.8 ml, 25.834 mmol) was dissolved in acetonitrile (25 ml), potassium carbonate (7.085 g, 51.267 mmol) and tert-butyl bromoacetate (5.000 g, 25.834 mmol) was boiled under reflux for 16 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc and washed with brine and water, dried with MgSO4 and evaporated under reduced pressure to give the desired product was obtained (6.00 g, yield 92.8%).