Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3].[N+]([O-])([O-])=[O:9].[In+3:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O>O>[OH-:1].[In+3:12].[OH-:9].[OH-:14].[O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3]
Reactant: O=[N+]([O-])[O-]
Agent: O=[Sb](=O)O[Sb](=O)=O
Agent: [In+3]
Solvent: O
Product: [OH-]
Temperature: 25 °C

Procedure:
900 g of water was added to 600 g of the diantimony pentoxide sol (specific gravity: 1,198, Sb2O5 concentration: 18.4 wt %) prepared in Preparation Example 1 for dilution. Then, an aqueous indium nitrate solution having 242.2 g of indium nitrate (In(NO3)3.3H2O, In2O3 content: 39.1 wt %, guaranteed reagent, manufactured by Mitsuwa Kagaku Yakuhin K. K.) dissolved in 200 g of water, was added thereto with stirring at room temperature. Then, the mixture was heated at 90° C. for 6 hours to obtain a mixed slurry of indium hydroxide and diantimony pentoxide. This slurry had an In2O3 concentration of 4.9 wt %, a Sb2O5 concentration of 5.7 wt % and an In2O3 /Sb2O5 molar ratio of 1.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=O)[C:11]([C:16]#[N:17])=[CH:12][NH:13]3)=[CH:8][C:7]=2[CH:19]=1.P(Cl)(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[Cl:31][C:10]1[C:9]2[C:14](=[CH:15][C:6]3[CH:5]=[C:4]([O:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:3]([O:2][CH3:1])=[CH:19][C:7]=3[CH:8]=2)[N:13]=[CH:12][C:11]=1[C:16]#[N:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCN1CCOCC1
Solvent: Cc1ccccc1
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCN1CCOCC1
Temperature: 25 °C

Procedure:
A mixture of 2.32 g (6.11 mmol) of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 35 mL of phosphorus oxychloride is heated under reflux for 1 hour, then cooled to room temperature. Excess phosphorus oxychloride is evaporated to yield a residue, to which toluene is added and the resulting solution is reduced in vacuo. Toluene is added and evaporated twice more. The resulting residue is cooled with ice bath, neutralized with cold saturated solution of sodium bicarbonate and stirred. The solid is collected by filtration, washed with cold water and dried to yield 1.989 g of 4-chloro-7-methoxy-8-(2-morpholin-4-yl-ethoxy)benzo[g]quinoline-3-carbonitrile as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:31])[CH2:18][CH:19]1[C:23]2[CH:24]=[C:25]([F:30])[C:26]([OH:29])=[C:27]([F:28])[C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:29][C:26]3[C:25]([F:30])=[CH:24][C:23]4[CH:19]([CH2:18][C:17]([OH:31])=[O:16])[CH2:20][O:21][C:22]=4[C:27]=3[F:28])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)CC1COc2c1cc(F)c(O)c2F
Product: O=C(O)CC1COc2c1cc(F)c(OCc1cccnc1SC1CCCC1)c2F
Yield: 0.7 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (19 mg, 0.08 mmol) obtained in Step C of Preparation Example 8 and (5,7-difluoro-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Preparation Example 51 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.25 mg, 72%).
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:11][C:10]=1[OH:27]>CCO>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:11]([CH2:1][N:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[C:10]=1[OH:27]
Reactant: C1CCNC1
Reactant: C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)c(F)cc21
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1ccc2c(CN3CCCC3)c(O)c(F)cc21

Procedure:
Paraformaldehyde (20.6 mg, 0.686 mmol) and pyrrolidine (0.057 ml, 0.686 mmol) in EtOH (1 ml) was heated until a clear solution was obtained. The solution was added to 6-fluoro-1-(phenylsulfonyl)-1H-indol-5-ol (100 mg, 0.343 mmol; Intermediate 95) in EtOH (1 ml) and the mixture was heated at 90 oC for 10 min. Solvent was evaporated. Yield: 137 mg and ca. 20% of material was purified on Gilson HPLC using 15-45% MeCN in 50 nM ammonium hydrogencarbonate buffer. Yield: 21 mg (82%); white solid. MS (ESI+) for C19H19FN2O3S m/z 375 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=O.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.[C:17]1([CH2:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N(C1CNC1=O)=[N+]=[N-]>ClCCCl.ClC(Cl)C.C(N(CC)CC)C>[C:1]([CH:2]1[N:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)[C:24](=[O:25])[CH:23]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(N)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [N-]=[N+]=NC1CNC1=O
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(c2ccccc2)C(=O)N1c1ccc(OC)cc1

Procedure:
To a solution of 17 ml of triethylamine and 5.0 g of the imine formed from ethyl glyoxalate and p-anisidine in 100 ml of refluxing 1,2-dichloroethane was added dropwise over 2 hours a solution of 16 ml of freshly distilled phenylacetyl chloride in 50 ml of dichloroethane. After refluxing for three hours the reaction was worked-up as per the 3-azidoazetidinone. The crude residue was chromatographed to yield the cis and trans isomers of 4-carboethoxy-1-(p-methoxyphenyl)-3-phenylazetidin-2-one as oils; cis: NMR (CDCl3): δ 7.2 (m, 7H), 6.7 (d, J=9, 2H), 4.7 (s, 2H), 3.6 (s, 3H), 3.6 (q, J=7, 2H), 0.7 (t, J=7, 3H); trans: NMR (CDCl3): δ 7.3 (m, 7H), 6.8 (d, J=9, 2H), 4.5 (d, J=2, 1H), 4.45 (d, J=2, 1H), 4.1 (q, J=7, 2H), 3.6 (s, 3H), 1.2 (t, J=7, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]=[C:20]=[O:21]>>[CH3:18][NH:19][C:20](=[O:21])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10]2
Reactant: CN=C=O
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Product: CNC(=O)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (55.8 mg, 0.248 mmol) using the same procedure employed for Example 2 (2), but with methylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (43.8 mg, 63%) having the following characteristics.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:38])([F:37])[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[N:20]1[CH2:36][CH2:35][C:23]2([CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH2:22][CH2:21]1>C(Cl)Cl>[CH2:27]1[C:23]2([CH2:35][CH2:36][N:20]([C:15]3[C:14]4[C:19](=[C:10]([C:9]([F:37])([F:38])[F:8])[CH:11]=[CH:12][CH:13]=4)[N:18]=[CH:17][CH:16]=3)[CH2:21][CH2:22]2)[CH2:24][CH2:25][NH:26]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc4c(C(F)(F)F)cccc34)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cccc2c(N3CCC4(CCNC4)CC3)ccnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (1 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(8-(trifluoromethyl)quinolin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.69 mmol, 1.0 eq.) in methylene chloride (4 ml) and the reaction mixture was stirred at 25° C. for 2 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-27).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:11][CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=3[Br:1])[CH2:6][CH2:7]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: OC1CCN(Cc2ccccc2Br)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3Br)CC2)cc1
Yield: 238.5 %

Procedure:
0.54 g (0.002 mol) of 1-(2-bromo-benzyl)-piperidin-4-ol and 1.23 ml (0.0088 mol) of triethylamine were dissolved in 4 ml of toluene, treated with 0.058 ml (0.0005 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:3). 0.463 g (60%) 1-(2-bromo-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: [NH:1]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:2]([C:8]([NH:10][C@@H:11]([C:24]([NH:26][C@H:27]([C:35]([O:37]CC1C=CC=CC=1)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15](C=O)[CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].CO.O>C1COCC1>[NH:1]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:2]([C:8]([NH:10][C@@H:11]([C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
A mixture of Boc-Gln-D-Trp(CHO)-Phe-OBzl (1.2 g) and 1N sodium hydroxide (3.6 ml) in a mixture of THF (30 ml), methanol (10 ml) and water (5 ml) was stirred for 1.5 hours. After adding water (10 ml), the organic solvent was evaporated. The resulting aqueous solution was washed with diethyl ether, acidified with 10% citric acid solution and allowed to stand in a refrigerator overnight. The precipitates were filtered, washed with water and recrystallized with a mixture of ethanol and water to give Boc-Gln-D-Trp-Phe-OH (0.80 g).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH:2]1[C:20]([O:22]CC)=[O:21].[Li+].[OH-]>CO>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH:2]([C:20]([OH:22])=[O:21])[NH:3][CH:4]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1=CNC(C(=O)OCC)Cc2c1[nH]c1ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1=CNC(C(=O)O)Cc2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
To a suspension of diethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-2,5-dicarboxylate (0.48 g, 1.46 mmol) in MeOH (6 mL) was added 4 N aqueous LiOH (1 mL) and the suspension was stirred for 2 hours at 20° C. Solvent was removed and the crude was dissolved in water (50 mL). The aqueous solution was then extracted with EtOAc (3×30 mL) and acidified with HOAc. Precipitate appeared and were collected by filtration and washed with water and EtOAc, then dried under high vacuum to give the title compound (300 mg); 1H-NMR (MeOH-d4): δ 8.06 (1H, s), 7.54 (1H, dd), 7.44 (1H, dd), 7.12 (2H, m), 4.43 (3H, m), 3.61 (1H, d), 3.41 (1H, m), 1.49 (3H,t); MS (ES): 301 (MH+).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[CH:24][N:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.ClCCl>[CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:28][C:26]2[CH:25]=[CH:24][N:23]=[C:22]([Br:21])[CH:27]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccnc(Br)c1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Brc1cc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)ccn1
Reaction time: 0.83 h
Yield: 69.4 %

Procedure:
A mixture of 904 mg of 4-benzhydryloxypiperidine synthesized in Production Example 1, 6.4 mL of dichloromethane, and 629 mg of 2-bromo-4-pyridinecarbaldehyde was stirred for 50 minutes. Sodium triacetoxyborohydride (1.075 g) was added thereto little by little, and the resulting mixture was stirred for 14 hours. The resulting mixture was diluted with ethyl acetate, and the diluted mixture was thrown into sodium bicarbonate water. The organic layer was collected by separation and washed with a saturated saline solution. The washed organic layer was dried over magnesium sulfate, and the solvent was distilled off. The resulting product was subjected to a silica gel column chromatography (hexane/ethyl acetate (volume ratio)=2:1 to 1:1) to give the title compound (1.027 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][O:34][CH2:35][O:36][CH3:37])([CH2:30][C:31]#[CH:32])[C:26]([O:28]C)=[O:27])=[C:18]([Cl:38])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C1COCC1.[OH-].[Na+]>O.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][O:34][CH2:35][O:36][CH3:37])([CH2:30][C:31]#[CH:32])[C:26]([OH:28])=[O:27])=[C:18]([Cl:38])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCC(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COCOC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#CCC(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COCOC)C(=O)O
Reaction time: 20 h
Yield: 99.9 %

Procedure:
The compound of Example 214 (1.12 g) was dissolved in a mixed solvent composed of MeOH:THF=1:1 (12 mL). To this solution, a 10% aqueous solution of sodium hydroxide (4 mL) was added and the mixture was refluxed. After 20 hours, the mixture was diluted with water, and hydrochloric acid was added to make the mixture acidic. The mixture was then extracted with ethyl acetate and the extract was washed with a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous magnesium sulfate. The solvent was removed to give the desired product as a yellow oil (1.09 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:14]([O:17][C:18]([NH:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH:15]=[CH2:16]>N1C=CC=CC=1>[CH2:14]([O:17][C:18]([NH:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:12])=[O:11])[CH:29]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1

Procedure:
3-Nitrophenylsulphonyl chloride was added at 0° C. to a solution of 11.6 g ethyl 3-{[(allyloxy)-carbonyl]-amino}-3-(3-aminophenyl)-propanoate from Example II.2.d in 110 ml of pyridine. After a reaction time of 2 h, the mixture was concentrated, 1 N hydrochloric acid was added, and the solution was extracted with dichloromethane. After drying the organic phase over magnesium sulphate, the solvent was removed and the crude product was purified by chromatography on silica gel (dichloromethane/methanol=40:1) to give 17.8 g of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][OH:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11])[CH:3]=1
Reactant: COCCCO
Reactant: N#Cc1ccc(Cl)cc1F
Product: COCCCOc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 3-methoxy-propanol analogously to the preparation of Intermediate 98.1 as a colorless solid; ES-MS: M+=230.1; HPLC: AtRet=2.81 min.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1>ClCCl.N1C=CC=CC=1>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCCC4)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Methyl-1H-indole-2-carbonyl chloride (109 mg, 0.6 mmol) in dichloromethane (2 mL) was added to N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-pyrrolidin-1-ylpropanamide (0.5 mmol) in pyridine (3 mL) at about 0° C. The ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed and residue was purified by reverse phase preparative HPLC to give the title compound as the acetate salt (116 mg, 37%). 1H NMR (DMSO, d6) δ 1.75 (m, 4H), 1.90 (s, 3H), 2.55 (m, 6H), 2.77 (t, 2H), 3.91 (s, 3H), 4.04 (s, 3H), 5.44 (s, 2H), 7.08 (d, 1H), 7.15 (t, 1H), 7.20 (s, 1H), 7.33(t, 1H), 7.35 (s, 1H), 7.55 (s, 1H), 7.59 (d, 1H), 7.71 (d, 1H), 7.91 (s, 1H), 7.99 (d, 1H), 9.51 (s, 1H), 10.14 (s, 1H). LCMS: MH+=567.3, Rt=2.579 min.(a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[CH:11]=[C:10]([CH3:20])[C:9]=2[CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=O>C(OC(=O)C)(C)(C)C>[C:5]([O:27][CH:21]([C:9]1[C:10]([CH3:20])=[CH:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:8])([CH3:6])[CH3:4]
Reactant: CCOC(=O)C(O)c1c(C)cc2cc(OC)ccc2c1-c1ccc(Cl)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2cc(OC)ccc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 105 %

Procedure:
To a solution of ethyl 2-(1-(4-chlorophenyl)-6-methoxy-3-methylnaphthalen-2-yl)-2-hydroxyacetate (27 mg, 0.07 mmol) in tert-butylacetate (1.0 mL) was added 70% perchloric acid (0.012 mL, 0.14 mmol) and the reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with solid sodium bicarbonate, water (2 mL) added and stirred 1 hour. The product was extracted with ethyl acetate, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give a colorless oil (16.2 mg). 1H-NMR: 400 MHz, (CDCl3) δ: 7.48 (s, 1H), 7.41-7.36 (m, 3H), 7.19 (d, J=6.4 Hz, 1H), 7.06 (d, J=9.2 Hz, 1H), 6.99 (br s, 1H), 6.86 (d, J=9.2 Hz, 1H), 5.00 (s, 1H), 4.12-4.02 (m, 2H), 3.82 (s, 3H), 2.52 (s, 3H), 1.13 (t, J=7.2 Hz, 3H), 0.91 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]([O:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OC(C)(C)C)[NH2:44]>B(F)(F)F.CCOCC.C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]2[O:32][CH:33]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:44]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2CC(=O)OCC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2nc(-c3ccc(F)cc3)co2)c(-c2ccc(F)cc2)s1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
(RS)-4-{1-[5-(4-Fluorophenyl)-2-methylthiazol-4-yl]-methanoyl}-3-[2-(4-fluoro-phenyl)-2-oxo-ethoxycarbonylmethyl]-piperazine-1-carboxylic acid tert-butyl ester, description 111 (0.385 g), tert-butyl carbamate (0.376 g) and boron trifluoride etherate (4 drops) were dissolved in xylene (5 ml) and heated to 140° C., under argon and with stirring for 48 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was dried (MgSO4), evaporated and the residue chromatographed over silica gel. Elution with a gradient of 25 to 100% ethyl acetate in hexane provided the title compound as a pale yellow oil (0.130 g), mass spectrum (API+) 581 [MH+], C30H30F2N4O4S requires 580.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17]O)[CH2:15][N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:27]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])([CH3:29])[CH3:28].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.CCOCC.CCCCCC>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:11][C@H:12]1[C@@H:16]([CH2:17][N:30]([CH:27]([CH3:29])[CH3:28])[S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[CH2:15][N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13]1)[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)N(C[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)N(C[C@@H]1CN(Cc2ccccc2)C[C@@H]1CN(C(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ((3S*,4R*)-1-benzyl-4-hydroxymethyl-pyrrolidin-3-ylmethyl)-isopropyl-carbamic acid tert-butyl ester (0.60 g, 1.66 mmol), N-isopropyl-2-nitro-benzenesulfonamide (0.49 g, 1.99 mmol), and PPh3 (0.52 g, 1.99 mmol) in toluene (15 mL), is added dropwise diisopropyl azodicarboxylate (0.39 mL, 1.99 mmol) at 0° C. under a nitrogen atmosphere. The solution is stirred for 1 h at room temperature, and then heated at 65° C. for 1 h. The reaction mixture is concentrated. The crude material is used purified by flash chromatography on silica gel (eluent: c-hexane/AcOEt 3:7) to give the crude product. To the solid product is added a mixture of Et2O/hexane (1:1) and the resulting suspension is filtered. The solid is washed with Et2O/hexane (1:1) solution, and then the combined filtrate is concentrated to give a titled product. TLC, Rf (AcOEt)=0.61. MS (LC-MS): 589.3 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.39 min.