Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:35])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]([C:29]([O:31]C)=[O:30])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1>C1COCC1.CO>[Cl:3][C:4]1[C:5]([F:35])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:33][CH3:34])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]([C:29]([OH:31])=[O:30])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
2N NaOH (1.3 ml, 2.66 mmol) was added to a solution of methyl (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylate (14) (0.252 g, 0.53 mmol) in THF (5 ml) and methanol (1 ml). The reaction mixture was stirred overnight at room temperature and evaporated to dryness. The residues were dissolved in water (10 ml) and the solution acidified to pH6 with 2N HCl. The resulting solids were collected by filtration, washed with water (5 ml) followed by diethylether (5 ml) and dried under vacuum to give (2S,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-1-methylpiperidine-2-carboxylic acid (15) as a cream solid (145 mg, 59%): 1H NMR Spectrum: (DMSO-d6) δ1.72-1.90 (2H, m), 2.20-2.31 (1H, m), 2.40-2.55 (1H+DMSO, m), 2.66 (3H, s), 2.84-2.94 (1H, m), 3.10-4.10 (2H, m), 3.95 (3H, s), 4.56-4.60 (1H, m), 7.18-7.25 (2H, m), 7.48-7.55 (2H, m), 8.05 (1H, s), 8.40 (1H, s); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: [NH2:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C(NC(C)C)(C)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl.[NH4+].[OH-]>C1(C)C=CC=CC=1.O>[CH2:8]([N:5]1[CH2:6][CH2:7][C:2]2([NH:1][C:25](=[O:27])[O:16][CH2:15]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NC1(CO)CCN(Cc2ccccc2)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C1NC2(CCN(Cc3ccccc3)CC2)CO1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a 1 L 4-neck round bottom flask was added (4-amino-1-benzylpiperidin-4-yl)methanol (21.86 g, 99 mmol) and diisopropyl amine (23.0 g, 249 mmol) in dry toluene (300 ml). The reaction mixture was cooled to 0° C. and a solution of triphosgene (35.57 g, 119 mmol) in toluene (100 ml) was added. The reaction mixture was heated to 60° C. for 1.5 h. After cooling to room temperature, the reaction mixture was diluted with water (200 ml), basified with aqueous NH4OH, and extracted with ethyl acetate (3×200 ml). The organic layers were combined and washed with two 200 ml portions of water and 200 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The solid was stirred in hexanes for 1.5 hours and filtered again to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][CH2:14][OH:15]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCC#Cc1ccc(C(F)(F)F)cc1Cl
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: OCCCc1ccc(C(F)(F)F)cc1Cl
Temperature: 65 °C
Reaction time: 11 h
Yield: 81.2 %

Procedure:
A suspension of Compound 71-1 (3.05 g) and chlorotris(triphenylphosphine)rhodium(I) (3.00 g) in toluene (80 ml) was stirred under a hydrogen atmosphere at 65° C. for 11 hr. The reaction mixture was concentrated, diisopropyl ether was added and the mixture was filtered through celite. The filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-70:30) to give the object product (2.52 g) as a brown oil.
Reaction SMILES: [NH2:1][C:2](=[S:14])[C:3]([NH:6]C(=O)OC(C)(C)C)([CH3:5])[CH3:4].Br[CH2:16][CH:17](OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH3:5][C:3]([CH3:4])([C:2]1[S:14][CH:16]=[CH:17][N:1]=1)[NH2:6]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reactant: COC(CBr)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: CC(C)(N)c1nccs1
Temperature: 120 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
A mixture of tert-butyl 1-amino-2-methyl-1-thioxopropan-2-ylcarbamate (5.31 g, 24 mmol), 2-bromo-1,1-dimethoxyethane (CAN:7252-83-7, 5.11 g, 30 mmol) and TsOH (0.49 g, 3 mmol) in acetic acid (50 mL) was stirred at 120° C. for 4 h. After evaporation of solvents, the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The water phase was washed with ethyl acetate (3×50 mL). Then water phase was lyophilized to give the title compound as brown solid (2.1 g, 65%); MS (LC/MS): 143.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]2[CH:28]=[CH:29][C:30]([N:35]3[CH:39]=[N:38][CH:37]=[N:36]3)=[C:31]([CH:34]=2)[CH:32]=O)[CH:23]=[N:22]1.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:32]1[C:31]1[CH:34]=[C:27]([C:24]2[CH:23]=[N:22][N:21]([CH3:20])[C:25]=2[CH3:26])[CH:28]=[CH:29][C:30]=1[N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: Cc1c(-c2ccc(-n3cncn3)c(C=O)c2)cnn1C
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(-n3cncn3)c(-c3nc4cc(-c5cnc(N)nc5)ccc4n3C(C)(C)C)c2)cnn1C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in DMF (10 mL) is added crude 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-[1,2,4]triazole-1-yl-benzaldehyde (112 mg, 0.42 mmol) at room temperature. Oxone (239 mg, 0.39 mmol) in H2O (1 mL) is added and the solution is stirred at the same temperature for 3 hours. Sat. sodium thiosulfate (10 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (10 mL). The combined organic layer is dried with MgSO4 (1 g) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (81 mg, 41%). LCMS (ESMS): m/z: 505.40 (M++1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].ClC1C=C(O)C=CC=1C=O.C(CC(Br)(C)C([O-])=O)C.[CH3:38][O:39][CH2:40][C:41]1[C:46]([C:47](O)=[O:48])=[CH:45][N:44]=[C:43]([C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=2)[N:42]=1.COC(=O)CC(=O)COC>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:47]([C:46]2[C:41]([CH2:40][O:39][CH3:38])=[N:42][C:43]([C:50]3[CH:51]=[CH:52][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:54][CH:55]=3)=[N:44][CH:45]=2)=[O:48])=[C:11]([Cl:17])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)c(Cl)c1
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Agent: CCCC(C)(Br)C(=O)[O-]
Agent: COCC(=O)CC(=O)OC
Agent: O=Cc1ccc(O)cc1Cl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2COC)c(Cl)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 4-methoxy-3-oxo-butyric acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[3-chloro-4-({[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][N:10]([CH:16]=O)[NH:11][C:12]([O:14][CH3:15])=[O:13].C([O-])(=O)C.[NH4+].C([NH2:26])=O.C(#N)C>O>[CH3:15][O:14][C:12](=[O:13])[NH:11][N:10]1[CH:9]=[C:8]([C:3]2[CH:4]=[N:5][N:6]([CH3:7])[C:2]=2[Br:1])[N:26]=[CH:16]1
Reactant: NC=O
Reactant: COC(=O)NN(C=O)CC(=O)c1cnn(C)c1Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)Nn1cnc(-c2cnn(C)c2Br)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Methyl 2-[2-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-oxoethyl]-2-formylhydrazine carboxylate (1.20 g, 3.76 mmol) was mixed with ammonium acetate (1.16 g, 15.0 mmol), formamide (4 mL) and acetonitrile (5 mL). The reaction was heated to 130° C., and the acetonitrile was allowed to boil off for 10 minutes. Heating was continued for an additional 4 hours. After addition of water, the crude mixture was extracted eight times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 100% [10% methanol in ethyl acetate] in heptane) afforded the product as a pinkish solid. Yield: 800 mg, 2.67 mmol, 19% over two steps. LCMS m/z 299.8 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.80 (br s, 3H), 3.90 (s, 3H), 7.52 (d, J=1.3 Hz, 1H), 7.77 (d, J=1.3 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[CH3:2].[C:20]([O:24][C:25](=[O:40])[C@H:26]([CH2:38][SH:39])[NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([S:39][CH2:38][C@H:26]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:40])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Reactant: CC(C)(C)OC(=O)[C@H](CS)NS(=O)(=O)c1ccc(Br)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCn1ccc2c(SC[C@H](NS(=O)(=O)c3ccc(Br)cc3)C(=O)OC(C)(C)C)nc(C)nc21
Temperature: 100 °C

Procedure:
279 mg of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) and 655 mg of N-(4-bromobenzenesulfonyl)-(R)-cysteine-tert-butyl ester (example 6b) were dissolved in 2 ml of NMP and 0.68 ml of DIPEA were added. The reaction mixture was heated to 100° C. for 4 h. The mixture was diluted with 60 ml of EE and extracted with 10% citric acid, saturated NaCl solution and with water. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The crude product was chromatographed on silica gel eluting with EE/toluene (1:6). Yield: 108 mg.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[O:15])[CH2:4]1.[C:27]([C:30]1[C:39]2[O:38][CH2:37][CH2:36][O:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)(=O)[CH3:28]>C1COCC1>[O:35]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:27]([NH:1][CH2:2][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C:14]([O:16][C:17]4[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=4)=[O:15])[CH2:4]3)[CH3:28])[C:39]=2[O:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CN)[C@@H](c3ccccc3)C2)cc1
Reactant: CC(=O)c1cccc2c1OCCO2
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CNC(C)c3cccc4c3OCCO4)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A 2.0 ml THF solution of 253 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-(aminomethyl)-4-phenylpyrrolidine-1-carboxylate and 144 mg of 5-acetylbenzodioxane was mixed with 0.12 ml of a boron trifluoride diethyl ether complex at 0° C. and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel chromatography (chloroform-methanol) to obtain 146 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-({[1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance. EP: 517.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([F:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[O:20][Si](CC)(CC)CC.[ClH:40].O1CCOCC1>O1CCCC1>[ClH:40].[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([F:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:33]=1)[OH:20]
Reactant: CC[Si](CC)(CC)O[C@@H](CNCCOc1ccc2c(c1)[nH]c1ccccc12)c1ccc(F)c(NS(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 102 (243 mg) was dissolved in anhydrous tetrahydrofuran (15 ml), whereto 4 N hydrogenchloride/1,4-dioxane (1 ml) was added and the mixture was agitated at room temperature for 1 hour. The deposited precipitate was taken out and washed with tetrahydrofuran, whereupon it was dried under a reduced pressure at 40° C., whereby the above-identified compound was obtained (96.8 mg).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([Zn][C:33]#[N:34])#N.Cl[C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([C:42]([O:44][CH3:45])=[O:43])=[N:40][CH:41]=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:41]([C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]([C:42]([O:44][CH3:45])=[O:43])=[N:34][CH:33]=1)#[N:40]
Reactant: COC(=O)c1ncc(Cl)cc1OC
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(C#N)cc1OC
Temperature: 120 °C
Yield: 86.7 %

Procedure:
In a 350-mL resealable vessel, Pd2dba3 (1.487 g, 1.623 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.444 g, 3.52 mmol), dicyanozinc (3.18 g, 27.1 mmol), and methyl 5-chloro-3-methoxypicolinate (step 1, 5.455 g, 27.1 mmol) were taken up in DMF (80 mL). The reaction mixture was purged with Argon and subsequently heated to 120° C. for 2 h. Upon cooling, the reaction mixture was concentrated under reduced pressure. The residue was filtered through Celite, and the filter cake was rinsed with 1% MeOH/DCM. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (33%-40% EtOAc/hexane) to afford the title compound as a white solid (4.51 g, 23.5 mmol, 87%). MS m/z=193 [M+H]+. Calculated for C9H8N2O3: 192. 1H NMR in CDCl3 δ: 8.51 (d, 1H, J=1.6), 7.55 (d, 1H, J=1.6), 4.00 (s, 3H), 3.97 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[CH:20]=[C:21]([C:28]([S:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[CH:29][N:30]=1)[C:22](N(OC)C)=[O:23])(=[O:17])=[O:16].C([O-])(O)=O.[Na+]>C1COCC1.Cl>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[S:15]([NH:18][C:19]1[CH:20]=[C:21]([CH:22]=[O:23])[C:28]([S:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([N:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)(=[O:40])=[O:39])=[CH:36][CH:37]=2)=[CH:29][N:30]=1)(=[O:17])=[O:16]
Reactant: CON(C)C(=O)c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Product: O=Cc1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.9 %

Procedure:
Lithium aluminium hydride (216 mg, 5.7 mmol) was added to a stirred solution of 2-(2,4-dichloro-benzenesulfonylamino)-N-methoxy-N-methyl-5-[4-(piperidine-1-sulfonyl) -phenylsulfanyl]-isonicotinamide (368 mg, 0.57 mmol) in THF (30 ml) and the reaction stirred for 90 minutes at room temperature. IN HCl solution (10 ml) was added cautiously and following 10 minutes of stirring NaHCO3 solution (40 ml) was added. The aqueous solution was extracted with ethyl acetate (2×40 ml), the combined extracts dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to afford 2,4-dichloro-N-{4-formyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide as a yellow oil (130 mg, 39%). 1H NMR (CDCl3); 10.25 (1H, s, COH); 8.53 (1H, s, py); 8.17 (1H, d, Ar); 7.57 (2H, d, Ar); 7.51 (1H, s, Ar); 7.42 (2H, m, py and Ar); 7.21 (2H, d, Ar); 2.89 (4H, m, 2×CH2N pip); 1.55 (4H, m, 2×CH2 pip); 1.34 (2H, m, CH2 pip).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)[N:6]2[N:5]=1)=O.[N:23]1([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>COCCO>[CH3:22][S:19]([C:15]1[CH:14]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:30]=4)=[N:5]3)=[CH:10][CH:11]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20]
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Reactant: Nc1cccc(N2CCOCC2)c1
Solvent: COCCO
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Yield: 29.8 %

Procedure:
2-Methanesulfinyl-7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0003727 mol) and 3-Morpholin-4-yl-phenylamine (183 mg, 0.00103 mol) were dissolved in 2-Methoxyethanol (3.2 mL) and the reaction was microwaved at 300 W at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 50.00 mg of [7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-morpholin-4-yl-phenyl)-amine as a lyophilated powder. (M+H)=450.15. 1H NMR (400 MHz, DMSO, d6) δ 9.40 (s, 1H), 9.04 (s, 1H), 8.51 (m, 2H), 7.95 (d, 1H, J=7.88 Hz), 7.80 (d, 1H, J=8.05 Hz), 7.34 (d, 1H, J=8.09 Hz), 7.26 (d, 1H, J=4.72 Hz), 7.22 (m, 2H), 6.99 (d, 1H, J=4.72 Hz), 6.61 (m, 1H), 3.68 (m, 4H), 3.28 (s, 3H), 2.99 (m, 4H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C1(B(O)O)C=CC=CC=1>O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: COc1cc(Br)ccc1C=O
Reactant: Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ccccc2)ccc1C=O
Temperature: 25 °C

Procedure:
A mixture of toluene (30 mL) and water (5 mL) was degassed with nitrogen for 30 min. A mixture of sodium carbonate (2.26 g, 6.9 mmol) was added followed by 2-methoxy-4-bromobenzaldehyde (0.5 g, 2.3 mmol), phenylboronic acid (0.337 g, 2.7 mmol) and tetrakis triphenyl phosphene palladium(0) (0.261 g, 0.022 mmol) to the above degassed water/toluene mixture. The reaction mixture was then refluxed overnight. After the reaction is completed, it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The obtained residue was purified by column chromatography using 3% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([CH3:16])[CH2:13][C@H:12]1[CH2:17][C:18](=[O:25])[CH2:19][C:20](OCC)=O)=O)C1C=CC=CC=1.C(OC(N1C[C@H](OC)C[C@H]1CC(=O)CC(OCC)=O)=O)C1C=CC=CC=1>>[CH3:16][CH:14]1[CH2:15][N:11]2[C@H:12]([CH2:17][C:18](=[O:25])[CH2:19][CH2:20]2)[CH2:13]1
Reactant: CCOC(=O)CC(=O)C[C@@H]1CC(C)CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)CC(=O)C[C@@H]1C[C@@H](OC)CN1C(=O)OCc1ccccc1
Product: CC1C[C@H]2CC(=O)CCN2C1
Yield: 34 %

Procedure:
In a similar manner to that described in Preparative Example 1(iii)′ above, a reaction was performed, using (2S)-1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)-4-methylpyrrolidine [obtained as described in Preparative Example 8(v)′ above] instead of (2S,4R)-1-benzyloxycarbonyl-2-(3-ethoxycarbonyl-2-oxopropyl)-4-methoxypyrrolidine, to give the title compound as a colorless oil (yield: 34%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])(=[O:33])=[O:32]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(CC(F)(F)F)cc1)C2=O
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: O=C1CC2(CCN(c3ccc(CC(F)(F)F)cc3)C2=O)CCN1S(=O)(=O)c1ccccc1Cl

Procedure:
This material was prepared as a white solid in analogy to example 3) from 2-(4-(2,2,2-trifluoroethyl)phenyl)-2,8-diazaspiro[4.5]decane-1,7-dione and 2-chlorobenzenesulfonyl chloride. MS (ESI): 501.08 (MH+).
Reaction SMILES: Cl.[F:2][CH:3]([F:14])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[OH:13].C(N(CC)CC)C.[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=O)[NH:28][C:27](=O)/[C:26]/2=[CH:35]/OC>CN(C)C=O>[I:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[N:28][CH2:27]/[C:26]/2=[CH:35]\[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH:3]([F:14])[F:2])=[C:6]([OH:13])[CH:7]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: NCc1ccc(OC(F)F)c(O)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Oc1cc(CN/C=C2\CN=Cc3ccc(I)cc32)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
An amount of 4-difluoromethoxy-3-hydroxy benzylamine hydrochloride (113 mg, 0.50 mmol), is dissolved in N,N-dimethylformamide (5 mL), triethylamine (50 μL 0.75 mmol) is added followed by (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (165 mg, 0.50 mmol). After the mixture is stirred at room temperature for 30 min, the solvent is removed in-vacuo and the residue dissolved in 7.5% methanol in chloroform and passed thru a short pad of Florisil eluting with 7.5% methanol in chloroform, the eluate is evaporated and the solid triturated with ether, filtered and washed several times with anhydrous ether to give 193 mg of (4Z)-6-Iodo-4-{[(4-difluoromethoxy-3-hydroxybenzyl)amino)methylene}isoquinoline-1,3(2H,4-dione as a beige solid (79% yield); mp 254-5° C., MS data ES(−) 485.0 m/e.