Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[CH3:18][N:19]([CH3:31])[CH2:20][CH2:21][N:22]([CH3:30])[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH2:21][CH2:20][N:19]([CH3:31])[CH3:18])[CH3:30])=[CH:28][CH:27]=1
Reactant: CN(C)CCN(C)c1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCN(C)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 54.1 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.28 g, 1.0 mmol) and N-[2-(dimethylamino)ethyl]-N-methylbenzene-1,4-diamine hydrochloride (0.30 g, 1.0 mmol) were stirred in N,N-dimethylformamide (5 mL) with triethylamine (0.6 mL). The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[[2-(dimethylamino)ethyl](methyl)amino]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (0.24 g, 55%) as a golden powder.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][O:13][C:14]1[C:15]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)=[N:16][CH:17]=[CH:18][CH:19]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-:49]>C1COCC1>[ClH:49].[CH3:26][C:24]1[N:25]=[C:21]([NH:20][C:15]2[C:14]([O:13][CH2:12][C:11]3[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][CH:27]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)[S:22][CH:23]=1
Reactant: [Cl-]
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(O[Si](C)(C)C(C)(C)C)c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncccc2OCc2cccc(O)c2)n1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A 125 mL round-bottomed flask was charged with 3-(3-(tert-butyldimethylsilyloxy)benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (5.4 g, 13 mmol) and THF (50 mL). TBAF (1M in THF, 15 mL, 15 mmol) was added and stirred at room temperature overnight. The reaction was poured into saturated aqueous NH4Cl and extracted with CH2Cl2 (2×100 mL). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified over silica gel (30 to 80% EtOAc in hexanes) to afford 3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenol hydrochloride (3.5 g, 79%) after HCl salt formation. 1H NMR (d6-DMSO) δ 9.83 (bs, 1H), 9.50 (bs, 1 h), 7.89 (dd, 1H), 7.38 (d, 1H), 7.22 (t, 1H), 6.98 (m, 2H), 6.91 (dd, 1H), 6.75 (dd, 1H), 6.62 (s, 1H), 5.22 (s, 2H), 2.29 (s, 3H). Mass spectrum (apci) m/z=314.1 (M+H-HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13](O)[C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15].S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]([Cl:23])[C:14]([CH3:19])([N+:16]([O-:18])=[O:17])[CH3:15]
Reactant: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(C(Cl)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Yield: 74.9 %

Procedure:
A mixture of 14.3 g of 1-(2,3,4-trimethoxyphenyl)-2-methyl-2-nitropropanol, 11.9 g of thionyl chloride and 150 ml of anhydrous benzene is refluxed for 3.5 hours. After the reaction, the reaction mixture is evaporated to remove solvent. The residue (yellow oil) is purified by silica gel chromatography (Solvent: n-hexane-ethyl acetate (10:1). 11.4 g of 1-(2,3,4-trimethoxyphenyl)-1-chloro-2-methyl-2-nitropropane are thereby obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.[Mg].O1CCOC1.[CH3:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>O1CCCC1>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([CH:22]([OH:23])[C:21]([CH3:25])([CH3:24])[CH3:20])=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC(C)(C)CO
Reactant: CC1(c2ccc(Br)cc2)OCCO1
Agent: [Mg]
Solvent: C1COCO1
Solvent: C1CCOC1
Product: CC1(c2ccc(C(O)C(C)(C)C)cc2)OCCO1
Reaction time: 8 h

Procedure:
In 250 milliliters of tetrahydrofuran, 118 grams of the above dioxolane is dissolved. One quarter of this solution is then added to 12 grams of magnesium, previously washed with chloroform, and refluxed with tetrahydrofuran for 20 minutes; and this mixture is refluxed 4 hours to initiate reaction. Additional dioxolane solution is thereafter added to maintain the refluxing without further heating. After the addition has been completed, 35 grams of 2,2-dimethylpropanol is added and the mixture is refluxed for 2 hours. The reactants are allowed to stand overnight and then poured onto ice-cold ammonium chloride solution. Tetrahydrofuran is added and the two layers formed are allowed to separate. The solvent layer is decanted off and the aqueous layer is extracted twice with 100 milliliters of tetrahydrofuran which are decanted off and combined with the remaining solvent layer. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to yield a yellow oil which is distilled at 120° to 150° C. and recrystallized from pentane/ether to yield 2-methyl-2-(4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)-1,3-dioxolane (m.p. 75°-80° C).
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=O)=[CH:13][CH:12]=1.[NH2:27][N:28]1[C@@H:32]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:31][CH2:30][C:29]1=[O:42]>O1CCCC1>[CH2:35]([O:34][CH2:33][C@@H:32]1[N:28]([N:27]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH2:17][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[C:29](=[O:42])[CH2:30][CH2:31]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NN1C(=O)CC[C@@H]1COCc1ccccc1
Reactant: Cc1cccc(C(=O)Cc2ccc(F)cc2)n1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(Cc2ccc(F)cc2)=NN2C(=O)CC[C@@H]2COCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
Boron trifluoride etherate (0.25 mL, 1.98 mmol) is added to a solution of 2-(4-fluoro-phenyl)-1-(6-methyl-pyridin-2-yl)-ethanone (0.45 g, 1.98 mmol) in tetrahydrofuran (6.6 mL) under nitrogen and stirred for 30 min. A solution of (R)-1-amino-5-benzyloxymethyl-pyrrolidin-2-one (0.43 g, 1.98 mmol) in tetrahydrofuran (1.0 mL) is added and the resulting mixture is stirred for 1 h. The mixture is concentrated in vacuo and the residue chromatographed on a SiO2 column (30% ethyl acetate/hexanes) to yield the title compound, 380 mg (45%), as a yellow foam.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]#[CH:4].CN(C)C=O.N1C=CN=C1.[CH2:24]([Si:26](Cl)([CH2:29][CH3:30])[CH2:27][CH3:28])[CH3:25]>CCOCC.O>[CH3:1][C:2]([O:13][Si:26]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:24][CH3:25])([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:3]#[CH:4]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CC(C)(O)CCc1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CC(C)(CCc1ccccc1)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The hydroxyl group is protected by treating 3.6 parts of 3-methyl-3-hydroxy-5-phenyl-1-pentyne in 15 parts by volume of dimethylformamide successively with 3.5 parts of imidazole and 4.0 parts of triethylsilyl chloride and stirring this mixture for 1 hour at room temperature. The reaction mixture is poured into ether/water and the ethereal layer is washed with water three times, dried over anhydrous sodium sulfate, and then the ether is removed at reduced pressure. Distillation of the residual oil provides 3-methyl-5-phenyl-3-triethylsilyloxy-1-pentyne.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@@H:38]([C:52](O)=[O:53])[CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:21]=[C:22]1[N:28]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C@H:38]([CH2:39][C:40]3[CH:45]=[C:44]([C:46]([F:49])([F:47])[F:48])[C:43]([NH2:50])=[C:42]([Cl:51])[CH:41]=3)[C:52]([N:4]3[CH2:3][CH2:2][N:1]([CH:7]4[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][CH2:8]4)[CH2:6][CH2:5]3)=[O:53])=[O:36])[CH2:31][CH2:30]2)[CH2:27][CH2:26][C:25]2[CH:55]=[CH:56][CH:57]=[CH:58][C:24]=2[NH:23]1
Reactant: CCOC(=O)CCCN1CCC(N2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
283 mg (1.00 mmol) ethyl 4-(4-piperazin-1-yl-piperidin-1-yl)-butyrate (Example A16b) were added to a mixture of 500 mg (0.90 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 321 mg (1.00 mmol) TBTU and 0.14 mL (1.00 mmol) triethylamine in 10 mL DMF and the reaction mixture was stirred for 2 h at RT. This was purified by HPLC without any further working up; the fractions containing the product were combined, evaporated down i. vac., the residue was stirred with saturated NaHCO3 solution, filtered and dried.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][NH2:4].C(O)(=O)[C:7](O)=[O:8].[F:12][C:13]([F:26])([F:25])[C:14]1[CH:24]=[CH:23][C:17]([O:18][CH:19]2[CH2:22][NH:21][CH2:20]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][CH:2]([CH3:5])[CH2:3][NH:4][C:7]([N:21]1[CH2:20][CH:19]([O:18][C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:25])[F:26])=[CH:24][CH:23]=2)[CH2:22]1)=[O:8]
Reactant: CC(C)CN
Reactant: O=C(O)C(=O)O
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A stirred solution of 3.6 g (0.022 mole) of 1,1-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen was treated with 1.6 g (0.022 mole) of 2-methylpropylamine (added via a syringe and needle through a septum placed in one neck of the reaction flask). After stirring for 1 hr, 6.2 g (0.02 mole) of 3-[4-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 30 min with 5 ml of triethylamine and stirring was continued for 18 hr. The reaction mixture was washed with water (2×25 ml), dried over magnesium sulfate, and concentrated in vacuo. The solid residue was recrystallized from ethanol/water, yielding 5.4 g (85.4%) of pale yellow crystals.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[C:28]([Cl:35])[CH:27]=1.C(N(CC)CC)C>ClCCCl>[CH3:23][O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]2[N:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:10]=[C:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12]3)=[O:34])=[C:28]([Cl:35])[CH:27]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: c1ccc(-n2nc3c(c2NC2CCCCC2)CCCC3)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N(c2c3c(nn2-c2ccccc2)CCCC3)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, cyclohexyl-(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amine (example 45) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of triethylamine for 120 h under reflux conditions to give the title compound as yellow solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C1(C#N)CCCC1.Cl.[C:15]([O:18]CC)(=[O:17])[CH3:16].[CH3:21][CH2:22][CH2:23][CH2:24]CC>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:16]1([C:15]([OH:18])=[O:17])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccccn2)CCCC1
Reactant: CCCCCC
Agent: Cl
Product: O=C(O)C1(c2ccccn2)CCCC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
In a sealed tube 1-pyridin-2-yl-cyclopentanecarbonitrile (3) (10 g, 58.14 mmol) and HCl (12N; 70 mL) were added at room temperature and the reaction mixture was stirred at 90° C. for 16 h while silica thin layer chromatography was performed (20% ethyl acetate/Hexane; Rf=0.1). The reaction mixture was concentrated; an azeotropically distilled with toluene and the residue was triturated with ether to get 1-pyridin-2-yl-cyclopentanecarboxylic acid (431) (10.5 g, 94%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:27]([Br:26])=[CH:31][S:30][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cscc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cscc2Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (4-bromo-3-thienyl)boronic acid (248 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (116 mg), the title compound was obtained as a pale-yellow oil (yield 470 mg, 92%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1>C(Cl)Cl>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])(=[O:23])=[O:22]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 94.9 %

Procedure:
To a solution of ethyl-3-aminobenzoate (50 mL, 333 mmol) and 2,6-difluorobenzenesulfonyl chloride (44.2 mL, 333 mmol) in DCM (300 mL) at 0° C. was added pyridine (32.2 mL, 400 mmol). The reaction mixture was warmed to rt, stirred for 36 h, and quenched with 2 mL NH3 (7 M in MeOH). The suspension washed with 10% NaHSO4 and the organic extracts combined and passed through a short column of silica gel. Residual material was flushed from the column with 10% MeOH/EtOAc. The organic extracts were combined and the solvent removed under reduced pressure to provide 107.9 g (95%) of the title compound of Step A. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.20 (s, 1H), 7.77 (s, 1H), 7.71 (t, J=7.4 Hz, 1H), 7.63 (d, J=7.3 Hz, 1H), 7.35-7.49 (m, 2H), 7.29 (t, J=9.3 Hz, 2H), 4.28 (q, J=7.1 Hz, 2H), and 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][C:34]([F:38])=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)=[O:28])[CH:22]=1.Cl.CC(O)C>C(OCC)C>[F:38][C:34]1[CH:33]=[C:32]2[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]3[CH:3]=[C:4]4[C:17](=[CH:18][CH:19]=3)[CH2:16][C@:6]3([C:14]5[C:9](=[N:10][CH:11]=[CH:12][CH:13]=5)[NH:8][C:7]3=[O:15])[CH2:5]4)[CH:22]=1)=[O:28])[CH2:30][CH2:31]2
Reactant: O=C(c1cc(Cl)ncn1)N1CCc2cc(F)ccc21
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: O=C(c1cc(Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2cc(F)ccc21

Procedure:
0.10 g (0.40 mmol) (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 0.11 g (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL 2-propanol and the mixture was refluxed for 4 h. Then the reaction mixture was diluted with diethyl ether, suction filtered and washed with diethyl ether. The precipitate was dissolved in DMF and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([CH2:12]O)[CH:11]=[C:6]2[C:5]([CH3:14])=[N:4]1)[CH3:2].S(Cl)([Cl:17])=O>C1C=CC=CC=1>[ClH:17].[Cl:17][CH2:12][C:10]1[CH:11]=[C:6]2[C:5]([CH3:14])=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1nc(C)c2cc(CO)cnc21
Solvent: c1ccccc1
Product: CCn1nc(C)c2cc(CCl)cnc21
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 11 g. of 1-ethyl-3-methyl-1H-pyrazolo-[3,4-b]pyridine-5-methanol (0.057 mol.), dissolved in 50 ml. of anhydrous benzene are added dropwise 55 ml. of thionyl chloride. A white suspension formed by this reaction is stirred for an additional three hours at room temperature. Then the slurry is sucked off, washed with benzene and dried at 70°, yield: 6.6 g. of 5-chloromethyl-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridine, hydrochloride (1:1); m.p. 154°-157°.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[N:6][N:5]=1)[CH3:2].[OH:12]O>C(O)(=O)C>[CH2:1]([S:3]([C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[N:6][N:5]=1)=[O:12])[CH3:2]
Reactant: CCSc1nnc(C(N)=O)s1
Reactant: OO
Solvent: CC(=O)O
Product: CCS(=O)c1nnc(C(N)=O)s1
Reaction time: 3 h

Procedure:
38 g of 5-ethylthio-1,3,4-thiadiazole-2-carboxamide are dissolved at 40° C. in 400 ml of glacial acetic acid and are then slowly reacted with 22.6 ml of a 30% hydrogen peroxide upon stirring. The solution is kept for another 3 hours at the same temperature. At the end of this period the oxidation is sufficiently complete not to require any further addition of heat. After standing overnight the reaction mixture is stirred into two liters of icewater resulting in the precipitation of a solid material which is removed by suction and recrystallized from isopropanol.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].[N:25]1([C:30](N2C=CN=C2)=[S:31])C=CN=C1.N>CN(C=O)C>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:30](=[S:31])[NH2:25])[CH2:21][CH2:20]2)=[O:14]
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=S)N1CCc2cccc(C(=O)Nc3nc4ccccc4s3)c2C1
Reaction time: 0.17 h

Procedure:
To a mixture of compound 1B (3.25 g, 8.50 mmol) in DMF (50 mL) was added TEA (4.71 mL, 34.0 mmol). The resulting mixture was stirred for 10 minutes and di(1H-imidazol-1-yl)methanethione (1.818 g, 10.20 mmol) was added. The reaction mixture was stirred at rt for 30 minutes. Ammonia (7 N in MeOH) (48.6 mL, 340 mmol) was added and the resulting mixture was stirred overnight. The reaction mixture was concentrated to remove the ammonia and MeOH. The DMF solution was directly used for the next step without further purification. LCMS (APCI): m/z 369 (M+H).
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([O-:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(Cl)(=O)C(C)(C)C.[CH2:40]([O:42][C:43]([C@@:45]1([NH:50][C:51]([C@H:53]2[NH:57][CH2:56][C@H:55]([O:58][C:59]([N:61]3[CH2:69][C:68]4[C:63](=[CH:64][CH:65]=[CH:66][C:67]=4[F:70])[CH2:62]3)=[O:60])[CH2:54]2)=[O:52])[CH2:47][C@H:46]1[CH:48]=[CH2:49])=[O:44])[CH3:41]>C1COCC1>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([N:57]1[C@H:53]([C:51](=[O:52])[NH:50][C@:45]2([C:43]([O:42][CH2:40][CH3:41])=[O:44])[CH2:47][C@H:46]2[CH:48]=[CH2:49])[CH2:54][C@@H:55]([O:58][C:59]([N:61]2[CH2:69][C:68]3[C:63](=[CH:64][CH:65]=[CH:66][C:67]=3[F:70])[CH2:62]2)=[O:60])[CH2:56]1)=[O:25])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1)C(=O)OCC
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N2Cc3cccc(F)c3C2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 98.4 %

Procedure:
A solution of 57.7 g (128 mmol) (S)-2-tert-butoxycarbonylamino-non-8-enoic acid dicyclohexylammonium salt (commercially available from Synthetech Oregon, USA) in 350 mL of THF was added dropwise to a solution of 15.1 g (125 mmol) pivaloyl chloride in 200 mL of THF while maintaining the temperature at 0-5° C. The dosing funnel was rinsed with 50 mL of THF and the suspension was stirred for 90 min at 5° C. jacket temperature. The temperature was decreased to −5° C. and 50.0 g (116 mmol) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester was added in five portions within 30 min to the mixed anhydride at −5° C. to 0° C. The funnel was rinsed with 25 mL of THF. The suspension was first stirred for 30 min at 0° C., then for 6 h at 23° C. After complete conversion 150 mL of water was added. The reaction mixture was concentrated at 50° C. jacket temperature under reduced pressure to a residual volume of 300 mL. After cooling to 23° C. 500 mL of toluene and 58 mL of aqueous HCl (1M) were added. The suspension was filtered and the reaction vessel and filter cake were washed with 220 mL of toluene. The phases of the filtrate were separated and the aqueous layer was extracted with 150 mL of toluene. The organic layers were washed separately with 200 mL of aqueous Na2CO3 (10 wt %) and 58 mL of aqueous HCl (1M). The combined organic layers were concentrated at 50° C. under reduced pressure using a rotary evaporator to afford 143.3 g of crude (54.5 wt %) 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropyl-carbamoyl)-pyrrolidin-3-yl ester in a yield of 98.4%.