Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.Cl[C:18]([O:20][CH3:21])=[O:19].CN(C1C=CC=CN=1)C.CCN(CC)CC>CCOC(C)=O>[CH3:21][O:20][C:18]([C:3]1[C:4](=[O:16])[S:5][C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:2]=1[OH:1])=[O:19]
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Reactant: COC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCC1(C)SC(=O)C(C(=O)OC)=C1O
Yield: 59.4 %

Procedure:
To 32 (91 mg, 0.37 mmol), methyl chloroformate (63 μL, 0.81 mmol), dimethylaminopyridine (DMAP) (23 mg, 0.18 mmol) and NEt3 (108 μL, 0.77 mmol) following General Procedure L was obtained 70 (66 mg, 59%, 79% based on recovered starting material) after flash chromatography (30% EtOAc/2% AcOH/Hexanes-10% THF/2% AcOH/EtOAc). 1H NMR (300 MHz, MeOD) δ 0.86 (t, J=6.9 Hz, 3H), 1.20 (bs, 12H), 1.35 (s, 3H), 1.55 (m, 1H), 1.71-1.75 (m, 1H), 3.59 (s, 3H); 13C NMR (75 MHz, MeOD) δ 13.3, 21.8, 24.4, 27.0, 28.5, 28.6, 29.0, 30.2, 31.0, 50.4, 58.3, 124.6, 168.1, 187.7, 196.7. HRMS (EI) m/z calculated for C15H24O4S+) 300.1389 obsd. 300.1375.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:44])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH2:35][O:36]C3CCCCO3)[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH2:35][C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:22]3[CH2:21][C:20](=[O:44])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-methyl-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M260) (6.20 g, 98.8 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (2.74 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1.CN1CCOCC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][N:36]=3)=[O:15])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(Cl)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.168 g, 0.506 mmol; Example 58D) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (0.404 mL, 0.809 mmol). After stirring for 30 minutes, the reaction was concentrated and dried under high vacuum for 10 minutes. The residue was dissolved in dichloromethane (0.5 mL) and 5-chloropyridin-2-amine (0.052 g, 0.404 mmol) and 4-methylmorpholine (0.089 mL, 0.809 mmol) were added. After 30 minutes, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 10% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.24-8.20 (m, 1H), 8.09 (d, J=8.8, 1H), 7.65 (dd, J=2.7, 8.8, 1H), 7.36-7.28 (m, 4H), 7.05-6.96 (m, 4H), 4.19 (s, 2H), 3.54 (t, J=6.5, 2H), 2.82 (t, J=6.5, 2H); MS (ESI+) m/z 442.0 (M+H)+.
Reaction SMILES: Cl.C(O)(=O)C.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([F:24])[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([O:29]CC)=[O:28])=[CH:14]2)[C:10]([CH3:32])=[CH:9][C:8]=1[F:33]>O>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([F:24])[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:32])=[CH:9][C:8]=1[F:33]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2C)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To 800 mg of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 160 mg of ethyl 1-(6-amino-5-fluoro-3-methylpyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 30 minutes. After adding 0.5 ml of distilled water, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 145 mg of the title compound as a pale brown powder.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[N:22]1[CH:23]=[CH:24][C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.1 %

Procedure:
Methanesulphonyl chloride (0.50 g) was added dropwise to a stirred solution of 1-(4-aminophenyl)-4-(4-pyridyl)piperazine (1.00 g) in dry pyridine (10 ml) at room temperature. The mixture was stirred at room temperature for 20 hours and then evaporated. The residue was dissolved in water and the solution was basified with sodium bicarbonate solution and allowed to stand for 2 hours. The solid was filtered off, washed with water, dried and crystallised from methanol/ethyl acetate to give the title compound (0.55 g), m.p. 230°-232° C. Found: C,57.80; H,6.07; N,16.89. C16H20N4O2S requires: C,57.81; H,6.06; N,16.85%.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:16])([F:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([F:16])[F:15])=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC(F)(F)c1ccccc1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
Heat at 60° C. a solution of 2,2-difluoro-2-phenyl-ethyl trifluoromethanesulfonate (759 mg, 2.617 mmol) and sodium azide (357 mg, 5.496 mmol) in anhydrous DMF (10 mL) under nitrogen for 3 h. Cool the reaction mixture to room temperature. Dilute with water and extract the aqueous phase twice with diethyl ether. Wash the combined organic extracts twice with ice-cold water, dry over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as an oil (475 mg, 99%) that was used without any further purification.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:8]=1>ClCCl>[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:8]=1
Reactant: COc1ccc(C(=O)O)c(-c2ccc(F)cc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccc(O)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of boron tribromide in dichloromethane (1M, 66 ml.) was added dropwise to a stirred solution of 4-methoxy-2-(4-fluorophenyl)benzoic acid (7.7 g.) in dried dichloromethane (215 ml) under an argon atmosphere at 0° C. The reaction was stirred for 1 hour at 0° C., allowed to warm to ambient temperature and stirred for 16 hours. The reaction was poured into ice water and extracted with dichloromethane followed by ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate and the aqueous phase acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracts were dried and evaporated to dryness to give 4-hydroxy-2-(4-fluorophenyl)benzoic acid (Compound xxx) as a yellow oil (4.5 g), which was used without further purification.
Reaction SMILES: [N:1]1([C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.O=[C:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.ClC(Cl)C>>[N:7]1[C:6]2[N:1]3[CH:2]=[CH:3][CH:4]=[C:5]3[C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Oc1cccnc1-n1cccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: O
Product: c1cnc2c(c1)OC1(CCNCC1)c1cccn1-2
Temperature: 130 °C
Yield: 93 %

Procedure:
A mixture of 2-pyrrol-1-ylpyridin-3-ol (1.00 g, 6.24 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (1.24 g, 6.24 mmol), 4-methylbenzenesulfonic acid hydrate (119 mg, 0.625 mmol), molecular sieves (442 mg) and dichloroethane (8.9 mL) was heated at 130° C. for 162 hours. The reaction was filtered and washed with dichloroethane. The solid was dissolved in MeOH and filtered through a plug of Celite. The solvent was evaporated under reduced pressure to yield spiro[piperidine-4,6′-pyrido[3,2-b]pyrrolo[1,2-d][1,4]oxazine] (1.4 g, 38%). ESI-MS m/z calc. 241.1. found 242.5 (M+1)+; Retention time: 1.10 minutes (4 min run).
Reaction SMILES: [CH2:1]([C:5]12[CH2:22][C:21](=[O:23])[C:20]([CH3:24])=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([CH3:15])[C:10]([O:16]COC)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.CCOC(C)=O>[CH2:1]([C:5]12[CH2:22][C:21](=[O:23])[C:20]([CH3:24])=[C:6]1[C:7]1[C:12]([CH2:13][CH2:14]2)=[C:11]([CH3:15])[C:10]([OH:16])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCc3c(ccc(OCOC)c3C)C1=C(C)C(=O)C2
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC12CCc3c(ccc(O)c3C)C1=C(C)C(=O)C2
Temperature: 80 °C

Procedure:
A solution of 3a-butyl-7-(methoxymethoxy)-1,6-dimethyl-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (63 mg, 0.19 mmol) in methanol (1.1 mL) was treated with aqueous 2N HCl (0.3 mL), placed under a N2 atmosphere, stirred, and heated in an oil bath at 80° C. for 35 minutes. After cooling, the mixture was diluted with EtOAc (25 mL) and washed with 5% NaHCO3 (10 mL). The organic phase was dried over MgSO4, filtered, and evaporated under vacuum to provide 3a-butyl-7-hydroxy-1,6-dimethyl-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: Clc1nccc(-n2ccnc2)n1
Yield: 101.9 %

Procedure:
In anhydrous tetrahydrofuran, 680 mg of 2,4-dichloropyrimidine was substituted with 680 mg of imidazole. The reaction mixture was then treated according to the procedure of Example 5 to yield 840 mg of the 2-chloro-4-(1-imidazolyl)pyrimidine, recrystallized from a mixture of n-hexane and ethyl acetate, having a melting point of 127.5°-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[O:14])[C:4]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=1.Br.C(S[C:31](=[NH:33])[NH2:32])C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:31]([N:11]1[CH2:10][CH2:9][CH:8]([N:6]2[CH2:7][C:3]([O:2][CH3:1])=[C:4]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[C:5]2=[O:14])[CH2:13][CH2:12]1)(=[NH:32])[NH2:33]
Reactant: CCSC(=N)N
Reactant: COC(=O)CCc1ccc(C2=C(OC)CN(C3CCNCC3)C2=O)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C2=C(OC)CN(C3CCN(C(=N)N)CC3)C2=O)cc1

Procedure:
Prepared from 4-methoxy-3-[4-(2-methoxycarbonyl-ethyl)phenyl]-1-(piperid-4-yl)-3-pyrrolin-2-one and S-ethylisothiourea-hydrobromide by heating to 100° C. for 4 hours in dimethylformamide in the presence of sodium carbonate.
Reaction SMILES: [C:1]1([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([N:52]3[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]3)=[N:48][CH:49]=[CH:50][N:51]=2)=[CH:42][CH:41]=1>ClCCl>[F:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C:47]([N:52]3[CH2:53][CH2:54][N:55]([C:13](=[O:15])[CH2:12][N:10]([CH3:11])[S:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)(=[O:8])=[O:9])[CH2:56][CH2:57]3)=[N:48][CH:49]=[CH:50][N:51]=2)=[CH:42][CH:41]=1
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CN(CC(=O)N1CCN(c2nccnc2-c2ccc(F)cc2)CC1)S(=O)(=O)c1ccccc1
Yield: 69 %

Procedure:
Dissolve (benzenesulfonyl-methyl-amino)-acetic acid (0.150 g, 0.654 mmol) in dichloromethane (5 mL). Add 1-hydroxybenzotriazole hydrate (0.081 g, 0.595 mmol) followed by 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.114 g, 0.595 mmol). Add 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.154 g, 0.595 mmol) and stir at ambient temperature for 18 hr. Add dichloromethane and water and separate layers. Extract the aqueous layer three times with dichloromethane. Dry the combined organic layers over magnesium sulfate, filter and concentrate under reduced pressure to give residue. Purify the residue by chromatography on silica gel eluting with 50-100% ethylacetate/hexanes to give the title preparation (193 mg, 69% yield). MS (ES+) m/z: 470 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29](O)=[O:30])[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:70]=[CH:69][C:66]([C:67]#[N:68])=[CH:65][CH:64]=1>>[C:67]([C:66]1[CH:69]=[CH:70][C:63]([NH:62][C:29]([CH:20]2[NH:19][CH:18]([CH2:32][C:33]([CH3:34])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:30])=[CH:64][CH:65]=1)#[N:68]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 53.7 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (0.95 g, 1.7 mmol), was reacted with diisopropylethylamine (1.8 g, 14 mmol), diphenylphosphinic chloride (1.6 g, 6.8 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.8 g, 6.8 mmol) to give rac-(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a white solid (Yield 0.5 g, 54%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([C:13]4([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCC1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cnc3[nH]cc(C(=O)C4(C)CCCCC4)c3n2)c1

Procedure:
[2-(3-Methoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclohexyl)-methanone and 3-methoxyphenyl boronic acid following general procedures as described in these Examples. MP 173-175° C., M+H=350.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1.[BH4-].[K+]>C(O)C.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1
Reactant: O=Cc1cnc(Nc2ccccn2)s1
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: OCc1cnc(Nc2ccccn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of 2-(pyridin-2-ylamino)thiazole-5-carbaldehyde (410 mg, 2 mmol) in ethanol (15 mL) and DMF (5 mL) was added potassium borohydride (120 mg). The resulting mixture was stirred at RT for 1 h, quenched with 10% sulfuric acid solution and concentrated in vacuo. The residue was extracted with methanol and the methanol solution was concentrated. The crude material was diluted with water, filtered and the solid was washed with water and dried in vacuo to provide compound 9A, [2-(pyridin-2-ylamino)thiazol-5-yl]methanol (385 mg, 93%) as a solid. LC/MS; (M+H)+=208
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl[C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=4)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:33][C:30]1[CH:31]=[C:32]2[C:27]([CH2:26][CH2:25][N:24]2[CH:21]2[CH2:22][CH2:23][N:18]([C:15]3[N:16]=[N:17][C:12]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:13][CH:14]=3)[CH2:19][CH2:20]2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Product: Cc1ccc(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)cc1

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 4-methylphenylboronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=O.Br[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]2>C(Cl)Cl>[CH:1]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:13][CH2:12]2)=[CH2:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2cc(Br)ccc2C1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TFA (0.7 mL, 9.07 mmol) was added dropwise to a solution of the product from step A (620 mg, 2.27 mmol) in DCM (10 mL). After stirring at room temperature for 4 h, the reaction mixture was evaporated to dryness. NEt3 (1 mL) was added to the residue and evaporated again to give the crude product, which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:34]C(=O)C)=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:34])=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Yield: 54.6 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,4,5-trimethoxyaniline (0.100 g, 0.185 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.101 mmol, 55%).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:28])=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH:21]=1>>[F:28][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: O=C1CCCN1c1cc(Br)ccc1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(N4CCCC4=O)c3)cnc2c1F
Yield: 31 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 1-(5-bromo-2-fluorophenyl)pyrrolidin-2-one as described in Example 6 to give 1-{2-fluoro-5-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]phenyl}pyrrolidin-2-one as a pale yellow solid (114 mg, 31%): m/z (ES+) 372 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[CH2:10]([S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH2:10]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[F:8])=[CH:17][CH:16]=1)(=[O:13])=[O:14])[CH3:11]
Reactant: Fc1ccc(Br)cc1I
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Br)ccc2F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a degassed, room temperature solution of 4-bromo-1-fluoro-2-iodobenzene (2.80 g, 9.30 mmol) and 4-(ethylsulphonyl)benzeneboronic acid (2.27 g, 10.6 mmol), in anhydrous 1,4-dioxane (120 mL) was added aqueous Na2CO3 solution (1M, 46.5 mL, 46.5 mmol) followed by the tetrakistriphenylphosphine palladium(0) (537 mg, 0.465 mmol). The slightly yellow solution was degassed 3 times by vacuum/nitrogen refill then was heated to 100° C. with stirring for 2 hours. The reaction mixture was cooled then suspended in CH2Cl2 (50 mL) and filtered through a pad of celite. The pad was rinsed well with CH2Cl2 (100 mL) and the filtrate was washed with water (2×50 mL) then dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to give crude product as a yellow oil. Purification by silica gel column chromatography eluting with heptane:EtOAc 1:1 afforded the title compound as a colourless oil in 84% yield, 2.696 g.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([Cl:12])[CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=3[CH3:13])[CH2:22][CH2:23]2)=[O:8])=[C:4]([Cl:12])[CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1cc(F)c(Br)cc1Cl
Product: Cc1ccc(N2CCN(C(=O)c3cc(F)c(Br)cc3Cl)CC2)c(C)c1
Yield: 101.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 1 and using 4-bromo-2-chloro-5-fluorobenzoic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (3.8 g), the title compound (8.5 g) was obtained.