Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1.C[Mg]Br.[F:25][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>O1CCCC1>[F:25][C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:21][C:13]=1[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:12])[CH:7]=1
Reactant: COc1ccc2c(c1)c(-c1cc3cccnc3[nH]1)cn2C
Reactant: F[B-](F)(F)F
Agent: C[Mg]Br
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(-c1[nH]c3ncccc3c1F)cn2C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.5 %

Procedure:
A solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine [0.1 g, Example 17(a)] in dry tetrahydrofuran (4 mL), at 0° C., was treated with methyl magnesium bromide (0.042 mL) and after stirring for a further 20 minutes at 0° C. this mixture was treated with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate) (0.13 g). The reaction mixture was stirred at room temperature for 4 hours, then stood at room temperature overnight, then heated at 40° C. for 4 hours, then heated at 80° C. for 2 hours, then cooled to room temperature and then partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate (25 mL). The combined extracts and ethyl acetate layer from the partitioning were washed with brine, then dried over magnesium sulfate and then evaporated. The residue was triturated with ethyl acetate to give the title compound (0.057 g) as a white solid, m.p. 248-250° C. 1H NMR [(CD3)2SO]: δ 12.20 (1H, s); 8.24 (1H, m); 7.81 (1H, s); 7.79 (1H, d, J=9.6 Hz); 7.46 (1H, d, J=9.6 Hz); 7.27 (1H, s); 7.18 (1H, dd, J=13.1, 6.0 Hz); 6.90 (1H, d, J=9.6 Hz); 3.88 (3H, s); 3.80 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].Cl[C:9](Cl)=[CH:10][N+:11]([O-:13])=[O:12]>CO>[N+:11]([CH:10]=[C:9]1[NH:1][CH2:2][CH2:3][CH2:4][S:5]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])C=C(Cl)Cl
Reactant: NCCCS
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
Into 40 ml of methanol was added 5.5 g of 1-amino-3-propanethiol, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, about 1/3-aliquot of a solution of 2.4 g of caustic soda dissolved in 20 ml of methanol was added dropwise thereinto, and the remainder of about 2/3-aliquot of the solution and a solution of 2.8 g of 2,2-dichloronitroethylene diluted in 10 ml of methanol were added dropwise slowly over 50 minutes, and the reaction was carried out for one hour. During the dropwise addition, the liquid temperature was maintained at lower than 10° C. (about 8° C.). After the reaction carried out for one hour, the procedure of the post-treatments as described in Example 1 was followed to obtain 2.96 g of tetrahydro-2-(nitromethylene)-1,3-thiazine (yield: 92.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].Br[CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCBr
Reactant: COc1cc[nH]c(=O)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1ccc(OC)c(C#N)c1=O
Temperature: 110 °C
Yield: 99.9 %

Procedure:
To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (20 g, 133 mmol) in acetonitrile (800 ml) were added 1-bromobutane (15.8 ml, 146 mmol) and potassium carbonate (36.7 g, 266 mmol) and the mixture was heated at 110° C. for 24 hours. The mixture was cooled to room temperature and the solid was filtered off The filtrate was evaporated till dryness and the resulting crude residue was then triturated with diethylether to yield pure intermediate 4 (27.39 g, >99%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10]([CH2:13][Br:14])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccn(C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ccc(CBr)n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
3-methyl pyrazole 1-carboxylic acid tert-butyl ester (4.0 g, 21.95 mmol) was dissolved in 73 mL of CCl4. N-bromosuccinimide (5.47 g, 30.73 mmol) and benzoyl peroxide (744 mg, 3.07 mmol) were added. This solution was warmed to reflux for 5.5 hours and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and saturated NaHCO3 solution. The phases were separated, and the organic phase was extracted with brine, dried over Na2SO4, filtered and concentrated to give a yellow oil. Purification by column chromatography (SiO2, ISCO chromatography system, elution with 5 to 10% ethyl acetate in hexanes) provided 3-bromomethyl pyrazole 1-carboxylic acid tert-butyl ester (53-2) as a pale yellow oil (2.94 g, 51% yield). 1H NMR was consistent with desired product.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]([CH2:19][CH3:20])[C@@H:12]([CH2:17]O)[C:13]([O:15]C)=[O:14])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>O1CCOCC1>[CH2:19]([N:11]([S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:10])=[O:9])[C:12](=[CH2:17])[C:13]([OH:15])=[O:14])[CH3:20]
Reactant: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C(=O)O)N(CC)S(=O)(=O)c1cccc(F)c1
Temperature: 80 °C
Yield: 24.3 %

Procedure:
A solution of 3F (3.0 g, 9.8 mmol) in dioxane (30 mL) was added with 20% NaOH aq. solution (20 mL) and the mixture heated at 80° C. for 5 h. The organic solvent was removed under reduced pressure and the aqueous phase acidified with 10% HCl. The solid formed was filtered under vacuum, washed with cold water (1×50 mL) and dried to afford 4F as white solid (650 mg, 25% yield). 1HNMR (DMSO, 200 MHz) δ 1.11 (t, 3H, J=7.7), 3.43 (q, 2H), 5.78 (s, 1H), 6.36 (s, 1H), 7.69 (m, 2H), 7.84 (m, 2H), 12.98 (bs, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27]>CC#N>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][NH:27][CH2:26][CH2:25][CH2:24][O:23][CH3:22])=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)OCCCc1ccc(Br)cc1
Reactant: COCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCNCCCc1ccc(Br)cc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A mixture of the product of step (i) (272 g, 0.93 mol), K2CO3 (256 g, 1.86 mol), methoxypropylamine (199 g, 2.22 mol) in MeCN (1.5 L) was stirred at 80-90° C. under N2 atmosphere for 16 hour. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated to remove MeCN. MTBE (1 L) and H2O (1 L) were charged to the resulting mixture and washed with aqueous 1N—HCl (1 L). The aqueous phase was collected and basified by aqueous 2.5N—NaOH to pH=9-10, to afford the subtitle compound (ii) in solution, which was used for next step directly.
Reaction SMILES: [Cl-].[Li+].O.[CH2:4]([C:12]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(C(OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]>CS(C)=O>[F:32][C:27]([F:33])([C:28]([F:29])([F:30])[F:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH:12]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 180 °C
Reaction time: 16 h
Yield: 78.8 %

Procedure:
Lithium chloride (401 mg, 9.540 mmol) and water (86 mg, 4.770 mmol) were added to a solution of diethyl 2-(7-octenyl)-2-(5,5,6,6,6-pentafluorohexyl)malonate (2.12 g, 4.770 mmol) in dimethyl sulfoxide (8 ml) followed by stirring for 16 hours at 180° C. After cooling, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/50) to give ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate (1.40 g, Yield 79%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])/[CH:15]=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:6][C:5]=1[CH3:10])=[O:3]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: COC(OC)N(C)C
Product: Cc1nc(N=CN(C)C)sc1C(=O)/C=C/N(C)C
Temperature: 100 °C

Procedure:
A mixture of 5-acetyl-2-amino-4-methylthiazole (12.5 g) and N,N-dimethylformamide-dimethylacetal (35.4 ml) is heated for 15 hours at 100° C. After cooling to room temperature the reaction mixture is evaporated, triturated with ethyl acetate, and filtered to give the title compound as an orange solid. MS (Method D) M+H 267.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH:21]([NH:24][C:25]1[C:26]2[N:27]([C:37]([O:40][CH3:41])=[N:38][N:39]=2)[C:28]2[C:33]([N:34]=1)=[CH:32][C:31]([CH:35]=O)=[CH:30][CH:29]=2)([CH3:23])[CH3:22].CC(O)=O>ClCCCl>[CH:21]([NH:24][C:25]1[C:26]2[N:27]([C:37]([O:40][CH3:41])=[N:38][N:39]=2)[C:28]2[C:33]([N:34]=1)=[CH:32][C:31]([CH2:35][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:30][CH:29]=2)([CH3:22])[CH3:23]
Reactant: C1COCCN1
Reactant: COc1nnc2c(NC(C)C)nc3cc(C=O)ccc3n12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1nnc2c(NC(C)C)nc3cc(CN4CCOCC4)ccc3n12
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
Solid sodium triacetoxyborohydride (59 mg) and morpholine (15 μL) were added to a solution of 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carbaldehyde (50 mg) in 1,2-dichloroethane (1.0 mL). The resulting suspension was stirred at 23° C. for 2.5 hrs., and then a portion of AcOH (10 μL) was added. After an additional 2.5 hrs., the reaction mixture was concentrated. The residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Silica gel chromatography afforded isopropyl-(1-methoxy-7-morpholin-4-ylmethyl-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-amine as a white solid. MS (M+H)+=357.5.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[N+:18]([O-])=O)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (3.4 g, 0.010 mol), ethanol (60 mL, 1 mol), and the solution was heated at 85° C. Ammonium chloride (6 g, 0.1 mol) in water (15 mL, 0.83 mol) was added followed by iron (2 g, 0.04 mol) in two portions. The reaction was stirred for 1 hour and poured onto dichloromethane (200 mL) and extracted. the solvent was removed under reduced pressureunder reduced pressure and the residue was purified by flash chromatography to afford the desired product as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[O:20]=[S:19]1(=[O:21])[CH2:18][CH2:17][CH2:16][N:1]1[C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=S(=O)(Cl)CCCCl
Product: O=C(O)c1ccc(C2(N3CCCS3(=O)=O)CC2)cc1

Procedure:
Using methyl 4-(1-aminocyclopropyl)benzoate (532 mg) and 3-chloropropane-1-sulfonyl chloride (0.44 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (559 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12

Procedure:
A 48 mL sealed tube was charged with (6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g, 1.72 mmol), phenylboronic acid (0.314 g, 2.58 mmol), cesium carbonate (1.68 g, 5.15 mmol), PdCl2(dppt)-CH2Cl2 adduct (0.0701 g, 0.0858 mmol), 1,4-dioxane (6.31 ml, 73.8 mmol), and water (1.11 ml, 61.8 mmol), flushed with argon, sealed, then placed in an 80° C. oil bath for 8 hours. The mixture was concentrated then triturated with water, followed by MeOH/DCM to give (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone as a reddish brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([NH:13][C@H:10]([C:8]2[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]3[CH:20]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][CH3:12])[N:25]=[CH:24][N:23]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Yield: 78.6 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine (62 mg, 0.23 mmol), 4-amino-6-chloro-5-cyanopyrimidine (36 mg, 0.23 mmol) and DIPEA (0.08 mL, 0.46 mmol) in IPA (2 mL) was heated for 6 h at 90° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in EtOAc) to afford 358 as a white solid (70 mg, 79%). LCMS (Method K): RT 4.10 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz): δ 7.81 (1H, s), 7.68 (1H, dd, J=8.8, 4.9 Hz), 7.56-7.44 (6H, m), 7.16 (2H, br s), 7.07 (1H, ddd, J=9.8, 8.8, 2.5), 6.79 (1H, dd, J=8.9, 2.5), 5.29 (1H, dt, J=7.7, 6.2), 1.97 (1H, dqd, J=14.9, 7.5, 6.2), 1.87 (1H, dqd, J=14.9, 7.5, 6.2), 0.75 (3H, t, J=7.5)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH3:11])=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][C:34]=1[Cl:35])[O:25][C@@H:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28]>CN(C=O)C.CCOC(C)=O>[Cl:35][C:34]1[CH:33]=[CH:32][C:24]([O:25][C@@H:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=1[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[CH:6][CH:5]=2)[C:10]([CH3:11])=[C:2]1[CH3:1]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(CBr)c1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1cc(O[C@@H](C)C(=O)OC)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the allyl 2,3-dimethyl-1H-indole-5-carboxylate (0.34 g, 1.483 mmol) in anhydrous DMF (3 mL) at 0° C. under argon protection was added NaH (0.08 g, 2.22 mmol). The mixture was stirred at rt for 30 min and re-cooled to 0° C., and then the (S)-methyl 2-(3-(bromomethyl)-4-chlorophenoxy)propanoate (0.55 g, 1.78 mmol) was added. The reaction was stirred at rt for another 1 h. The solvent was removed to obtain the crude, which was dissolved in EtOAc, then washed with water and brine and dried over Na2SO4. The solvent was removed to obtain the crude. The crude was purified by flash chromatography (AcOEt/Hexane 0-100%) to obtain the title compound. ESI-MS (m/z): 456 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:28][C:29](=[O:39])[CH2:30][C:31]([C:33]1[S:34][CH:35]=[CH:36][C:37]=1[Cl:38])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:21]([O:20][C:17]1[N:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:31]([C:33]4[S:34][CH:35]=[CH:36][C:37]=4[Cl:38])[CH2:30][C:29](=[O:39])[NH:28][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OCc3ccccc3)nc2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccc(OCc4ccccc4)nc3)cc2N1
Yield: 27.5 %

Procedure:
Prepared from {4-(6-benzyloxy-pyridin-3-yl)-2-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K26) (172 mg, 0.3 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (38 mg).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[C:10]([CH:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])#[N:11]
Reactant: COC(=O)CCCCBr
Reactant: N#CCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCC(C#N)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 8.6 g of sodium hydride (50% dispersion in mineral oil) in 200 mL of dimethylformamide is added in a solution of 17.7 g of 3-pyridylacetonitrile in 15 mL of dimethylformamide over a period of 0.5 hour. The reaction is stirred for a further 0.5 hour at room temperature, then cooled to -20° before adding 30 g of methyl 5-bromovalerate. The reaction is then allowed to warm up to room temperature over a period of several hours and left to stand for 18 hours. The reaction is then poured into 300 mL of ice water and extracted with 300 mL of ethyl acetate. The extract is washed with 3 portions of 75 mL of 1N hydrochloric acid and the aqueous solution neutralized with ammonium hydroxide and extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered and evaporated to yield methyl 6-cyano-6-(3-pyridyl)-hexanoate.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[NH:22][C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=2)[C:26]([O:28]CC)=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.O>[C:12]1([C@H:9]2[CH2:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]2[C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[NH:22][C:23]2[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=2)[C:26]([OH:28])=[O:27])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1c1ccccc1)Nc1cccc(C(=O)O)c1
Yield: 70.9 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 3 g of ethyl (cis)-3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoate in solution in 50 cm3 of methanol and 0.7 g of potassium hydroxide dissolved in 20 cm3 of water and after treatment and recrystallization in ethanol, 2 g of (cis)-3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 255° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([NH2:33])([CH3:32])[CH2:30][CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=2)[NH:33][C:29]([CH3:32])([CH3:28])[CH2:30][CH3:31])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NC(SC)=C(C#N)S(=O)(=O)c2ccc(Cl)cc2)cc(OC)c1
Reactant: CCC(C)(C)N
Product: CCC(C)(C)NC(Nc1cc(OC)cc(OC)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 26 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3,5-dimethoxyphenylamino)-3-methylsulfanyl-2-propenenitrile (0.30 g, 0.7 mmol) was stirred in 1,1-dimethylpropylamine (1 ml) for 17 h at 100° C. in a sealed flask under nitrogen. Work-up as described in Example 17, 2) without chromatography gave 84 mg (26%) of the title compound. Mp 189-190° C. 1H NMR (200 MHz, CDCl3): δ=0.95 (t, 3H), 1.35 (s, 6H), 1.65 (q, 2H), 3.62 (s, 6H), 6.20 (t, 1H) 6.45 (br s, 1H), 7.0 (br s, 1H), 7.50 (dt, 2H), 7.83 (dt, 2H); Analysis: calc. for C22H26ClN3O4S: C, 59.96%; H, 5.65%; N, 9.06%. Found: C, 56.82%; H, 5.64%; N, 8.90%.