Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][C:29]([O:32][CH3:33])=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].[CH3:38]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:38])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][C:29]([O:32][CH3:33])=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:34]([F:37])([F:35])[F:36]
Reactant: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: ClCCl
Product: COc1ncc(Cc2cn(C)c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (crude) (410 mg, 0.769 mmol) in DCM (1.5 mL) was added DIPEA (0.269 mL, 1.539 mmol) and MeI (0.072 mL, 1.154 mmol). The mixture was stirred at room temp overnight. Purification via MDAP then afforded the title compound (120 mg, 28.5% yield). LCMS: rt=3.48 min, [M+H+]=547
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)(C)[CH3:9])=[CH:4][CH:3]=1.[OH-].[Na+].C1([OH:26])C=CC=CC=1>[Hg]>[C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[OH:26])([CH3:11])=[CH2:9]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Oc1ccccc1
Agent: [Hg]
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)c1ccccc1O
Reaction time: 0.83 h

Procedure:
A distillation flask equipped with a Vigreux column was charged with 70.0 g. (0.31 mole) of bisphenol A [2,2-bis(p-hydroxyphenyl)propane] and 0.2 g. of sodium hydroxide. The bisphenol A was pyrolyzed under reduced pressure at a bath temperature of 200° to 270° C. Over a period of about 50 minutes and under 10 mm. of pressure (mercury) a distillate of 68.1 g. of a mixture of phenol and isopropenylphenol was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[OH:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([O:31][CH3:32])=[O:30])=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:43]1[CH:48]=[CH:47][CH2:46][CH2:45][CH2:44]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[C:1]([O:5][C:6]([N:8]([CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[O:35][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([O:31][CH3:32])=[O:30])=[CH:22][N:23]3[CH:26]([CH3:27])[CH3:28])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cn(C(C)C)c2cc(-c3ccc(CCN(C[C@H](O)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cn(C(C)C)c2cc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc12

Procedure:
To a solution of methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylate (340 mg) in dichloromethane (5 ml) were added 3,4-dihydro-2H-pyran (0.105 ml) and a catalytic amount of pyridinium p-toluenesulfonate at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylate (310 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(Cl)c1

Procedure:
1.0 g (5.21 mmol) of 3,4-dichloronitrobenzene (Fluka, Buchs, Switzerland), 532 mg (7.81 mmol) imidazole (Aldrich, Buchs, Switzerland) and 1.35 g (10.4 mmol) Hünig's base in 4 ml of DMA are heated in a microwave oven at 180° C. for 1 h 40 min. The reaction mixture is quenched with sat. aqueous NaHCO3 and extracted with EtOAc (2×). The organic layers is washed with sat. aqueous NaHCO3 (3×), with brine, dried over MgSO4, filtered and evaporated. The residue is purified by flash chromatography on silica gel (CH2Cl2-MeOH 1:0 to 93:7) to provide the title compound as an oil. ES-MS: 224 (M+H)+; analytical HPLC: tret=2.11 minutes (Grad 1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH:25]([NH2:28])([CH3:27])[CH3:26]>ClCCl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 2.5 °C
Yield: 82940.7 %

Procedure:
2-Fluoro-4-nitrobenzoic acid (1.002 g, 5.41 mmol) was dissolved in dichloromethane and cooled in an ice bath. DMF (0.1 mL) and oxalyl chloride (0.71 mL, 8.4 mmol) were added, and the reaction mixture was stirred at ice bath temperature (0-5° C.) for two houres. Dichloromethane (25 mL) was added, followed by isopropylamine (1.85 mL, 21.7 mmol). The ice bath was removed and the reaction mixture was stirred for 2.5 hours. The reaction mixture was washed with 25 mL of 10% aqueous NaOH solution, and the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (EtOAc/hexanes 0-33%) to give 1,015 g of 2-fluoro-N-isopropyl-4-nitro-benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Br:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:25])/[CH:15]=[CH:16]/[C:17]1[S:21][C:20]([CH:22]([CH3:24])[CH3:23])=[N:19][CH:18]=1.CC#N.CC(O)=O.OP(O)(O)=O>[Cl-].[Cl-].[Zn+2].O>[Br:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[S:21][C:20]([CH:22]([CH3:23])[CH3:24])=[N:19][CH:18]=4)[CH2:15][C:14](=[O:25])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)/C=C/c3cnc(C(C)C)s3)c(N)c2c1Br
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2oc3c(c2c1Br)NC(c1cnc(C(C)C)s1)CC3=O
Temperature: 90 °C
Yield: 79.1 %

Procedure:
A mixture of 14A (1.4 g, 3.3 mmol), ZnCl2 (6 g), MeCN (10 mL), AcOH (2 mL) and H3PO4 (2 mL) was heated to 90° C. and reacted overnight. TLC monitored the reaction. After the reaction completed, the reaction mixture was added dropwise into water, extracted with ethyl acetate and concentrated to give 14B (1.1 g, 78% yield).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[CH:11]=[C:10]2[C:17]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:16][N:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][OH:3])=[CH:15][CH:14]=2)[C:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11]1
Reactant: CCOC(=O)COc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(OCCO)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
A solution of {1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yloxy}-acetic acid ethyl ester [120 mg, Reference Example 15(b)] in dry tetrahydrofuran (5 mL) was treated with lithium aluminium hydride (1.0M solution in tetrahydrofuran, 50 μl) at 0° C. under a nitrogen atmosphere. The mixture was allowed to warm to ambient temperature, then stirred for 3 hours and then carefully poured into water (75 mL). The mixture was extracted three times with ethyl acetate (25 mL). The combined organic extracts were washed with brine (75 mL), then dried over sodium sulfate and then evaporated to give the title compound (45 mg) as a colourless solid, m.p. 209-210° C. MS: 308 (MH+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N:13]1([CH2:18][C:19]#[C:20][C:21]([OH:23])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[NH2:24][C:25]1[CH2:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[C:28]2[CH:39]=[C:40]([CH2:46][CH3:47])[C:41]([S:43][CH2:44][CH3:45])=[CH:42][C:27]=2[N:26]=1>O1CCCC1.CN(C)C=O>[CH2:44]([S:43][C:41]1[C:40]([CH2:46][CH3:47])=[CH:39][C:28]2[C:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=3)=[N:30][CH2:31][C:25]3[N:26]([C:19]([CH2:18][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)=[CH:20][C:21](=[O:23])[N:24]=3)[C:27]=2[CH:42]=1)[CH3:45]
Reactant: O=C(O)C#CCN1CCCC1
Reactant: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCC(N)=N2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCSc1cc2c(cc1CC)C(c1ccc(C)cc1)=NCc1nc(=O)cc(CN3CCCC3)n1-2

Procedure:
In the manner given in Example 21, carbonyldiimidazole, 4-(1-pyrrolidinyl)tetrolic acid, and 2-amino-8-ethylthio-7-ethyl-5-(p-methylphenyl)-3H-1,4-benzodiazepine was stirred in tetrahydrofuran-dimethylformamide to give 10-ethylthio-9-ethyl-1-(1-pyrrolidinylmethyl)-7-(p-methylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [NH2:1][C:2](=[S:15])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[S:6][C:7]=1[CH3:8].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)=O>>[OH:26][C:22]1[CH:21]=[C:20]([C:18]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH:12]([CH3:13])[CH3:14])=[O:10])[S:6][C:7]=3[CH3:8])[S:15][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: O=C(CBr)c1cccc(O)c1
Reactant: Cc1sc(C(=O)OC(C)C)cc1C(N)=S
Product: Cc1sc(C(=O)OC(C)C)cc1-c1nc(-c2cccc(O)c2)cs1

Procedure:
A solution of 1.97 g (8.1 mmol) of isopropyl 4-(aminothioxomethyl)-5-methylthiophene-2-carboxylate was reacted with 1.74 g (8.1 mmol) of 3′-hydroxy-2-bromoacetophenone (Example 40, step (a)) were reacted in a manner similar to Example 8, step (a) to give, after column chromatography on silica gel eluting with hexane:ethyl acetate 7/3 (v:v), crystallization from acetonitrile, and recrystallization from hexanes, isopropyl 4-[4-(3-hydroxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiophene-2-carboxylate (1.4 g, 48%) as brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.57 (br s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.46 (m, 2H), 7.26 (m, 1H), ), 6.78 (m, 1H), 5.12 (septet, 1H, J=6.2 Hz), 2.85 (s, 3H), 1.33 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C18H17NO3S2 360.1 (M+H), found 360.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C>[N:28]1[CH:29]=[CH:30][C:25]([CH:23]=[CH:24][C:2]2[CH:3]=[C:4]([O:9][CH2:10][C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=2[Cl:8])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=Cc1ccncc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Yield: 68.3 %

Procedure:
A mixture of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (1.18 g, 3 mmol), 4-ethenylpyridine (0.39 mL, 3.6 mmol), Pd(OAc)4 (62.5 mg), tris(o-tolyl)phosphine (312.5 mg), and triethylamine (6.25mL) in acetonitrile (15 mL) was heated at reflux for 16 hours. The solution was then concentrated, and the residue was washed with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:5-100:15 to afford the title compound (852 mg, 69% yield). MS (CI/NH3) m/z 416 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.48 (s, 9H), 1.92 (m, 2H), 2.02 (m, 2H), 3.42 (m, 2H), 3.97 (m, 1H), 4.13 (m, 2H), 7.43 (m, 2H), 7.56 (m, 1H), 8.05 (m, 1H), 8.62 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH:13]=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([N:23]2[CH2:27][CH2:26][C@@H:25]([N:28]3[CH2:32][CH2:31][CH2:30][C@@H:29]3[CH3:33])[CH2:24]2)[N:17]=1>>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:22][C:21]2[C:16]([CH3:15])=[N:17][C:18]([N:23]3[CH2:27][CH2:26][C@@H:25]([N:28]4[CH2:32][CH2:31][CH2:30][C@@H:29]4[CH3:33])[CH2:24]3)=[CH:19][CH:20]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: COC(=O)C1(CCC=O)CCOCC1
Product: COC(=O)C1(CCCNc2ccc(N3CC[C@@H](N4CCC[C@@H]4C)C3)nc2C)CCOCC1

Procedure:
The title compound was synthesized in essentially the same manner using the procedures as set forth in Step 1 of Example 1, by condensing 4-(3-oxo-propyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (44 mg, 0.22 mmol) and 2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine to obtain 84 mg of a crude solid, which was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[CH:21])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: Brc1ccccn1
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1F
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1ccccn1)c1ccc(F)cc1F
Yield: 60.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 244(C), from tert-butyl 2,4-difluorophenyl(pent-4-ynoyl)carbamate (250 mg, 0.82 mmol) and 2-bromopyridine (129 mg, 0.82 mmol). The crude residue was purified over silicagel chromatography (prepacked 25 g silicagel column cyclohexane/AcOEt: 70/30 as eluent) to afford 193 mg of tert-butyl 2,4-difluorophenyl(5-(pyridin-2-yl)pent-4-ynoyl)carbamate as a brown oil (Yield: 61%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CS(C)=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[CH:25]1[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:27][CH2:26]1
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.406 g, 2.13 mmol) and 7-chloro-3-(piperidin-4-yl)-1H-indole (0.500 g, 2.13 mmol) using ethanol as reaction solvent. Yield 0.325 g (35%) as a colorless powder. mp 186°-189° C. FDMS m/e=423 (M+ of free base). α[D]589 =+8.44 (c=1.09, dimethylsulfoxide).
Reaction SMILES: Cl.[C:2]([C:4]1([CH3:8])[CH2:7][NH:6][CH2:5]1)#[N:3].N1CCCC1.CC(O[C:19]([NH:21][C@@H:22]([C:26]([OH:28])=O)[CH:23]1[CH2:25][CH2:24]1)=[O:20])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH3:45][N:46]1[CH:50]=[C:49]([C:51]2[N:56]=[C:55]3[C:57](C(O)=O)=[CH:58][N:59](COCC[Si](C)(C)C)[C:54]3=[N:53][CH:52]=2)[CH:48]=[N:47]1.C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)CO>>[C:2]([C:4]1([CH3:8])[CH2:7][N:6]([C:26](=[O:28])[C@H:22]([NH:21][C:19]([C:57]2[C:55]3[C:54](=[N:53][CH:52]=[C:51]([C:49]4[CH:48]=[N:47][N:46]([CH3:45])[CH:50]=4)[N:56]=3)[NH:59][CH:58]=2)=[O:20])[CH:23]2[CH2:24][CH2:25]2)[CH2:5]1)#[N:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: Cn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: CC1(C#N)CNC1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: C1CCNC1
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CC(C)(C#N)C4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 3-cyano-3-methyl-azetidine hydrochloride for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. N-Boc deprotection in step 2 was achieved using 2,2,2-trifluoroethanol in a microwave reactor. MS: (M+H)+=419.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[CH:16]=[CH:15][C:12](CO)=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[C-:17]#[N:18].[Na+].O.[CH3:21]COCC>>[CH2:6]([CH:5]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:15][CH:16]=1)[C:17]#[N:18])[CH2:7][CH2:8][CH3:21]
Reactant: CCCCc1ccc(CO)cc1
Reactant: [C-]#N
Reactant: CCOCC
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCC(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (4.7 ml, 66 mmol) was added dropwise to a solution of 4-n-butylbenzyl alcohol (9.6 g, 59 mmol) in ether (120 ml), and this mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and excess thionyl chloride was removed by azeotropic distillation with benzene. The residue was dissolved in dimethyl sulfoxide (50 ml), sodium cyanide (86 g, 1.8 mol) and n-tetrabutylammonium iodide (2.2 g, 5.9 mmol) were added to this solution, and the resulting mixture was stirred at room temperature for 16 hours. Water was added, and this mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give n-butylphenylacetonitrile (8.2 g) as a yellow oil. Next, concentrated sulfuric acid (48 ml) was added dropwise to water (58 ml), this solution was cooled to 50° C., and n-Butylphenylacetonitrile (8.2 g) obtained above was added dropwise to the solution. The resulting mixture was stirred while heating under reflux for 16 hours. Upon cooling to room temperature, the precipitated crystals were collected by filtration, washed with water, and dissolved in a 0.1 N aqueous sodium hydroxide solution (200 ml). Norit (5 g) was added, and this mixture was stirred and refluxed for 2 hours. After Norit was removed by filtration through celite, the filtrate was cooled to room temperature and acidified with 1 N hydrochloric acid to precipitate crystals. The precipitated crystals were collected by filtration, washed with water, and dried to give the title compound (3.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([C:12]([F:15])([F:14])[F:13])[CH:4]=1.S(Cl)(Cl)=O.COC1C(C(F)(F)F)=CC(C(Cl)=O)=CC=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[S:43][C:44]3[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:45]=3[N:46]=2)=[CH:38][CH:37]=1>N1C=CC=CC=1>[F:13][C:12]([F:15])([F:14])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[S:43][C:44]3[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[CH:47][C:45]=3[N:46]=2)=[CH:40][CH:41]=1)=[O:9]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: COc1ccc(C(=O)O)c(C(F)(F)F)c1
Agent: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(-c3nc4ccc(OC)cc4s3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A stirred mixture of 4-methoxy-2-trifluoromethylbenzoic acid (0.50 g, 2.27 mmol) and thionyl chloride (9 ml) was heated under reflux for 4 h. After cooling to room temperature, the excess reagent was removed under reduced pressure to give crude acid chloride. The amide was prepared as described in the Amide Coupling section using the crude 4-methoxy-5-trifluoromethylbenzoyl chloride and 2-(4-aminophenyl)-6-methoxybenzo thiazole (0.58 g, 2.27 mmol) in dry pyridine (15 ml) to give the title compound (0.478 g, 46%) as pale yellow needles after work-up and recrystallisation from acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][NH:11]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:23]1[CH2:27][CH2:26][CH:25]([CH2:28][C:29](Cl)=[O:30])[CH2:24]1.O>C(Cl)Cl>[CH:25]1([CH2:28][C:29]([N:11]2[C@@H:12]3[C@@H:8]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:15]=4[CH2:14][CH2:13]3)[CH2:9][CH2:10]2)=[O:30])[CH2:26][CH2:27][CH2:23][CH2:24]1
Reactant: COc1cccc2c1CC[C@@H]1NCC[C@H]21
Reactant: O=C(Cl)CC1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1C(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
5.0 g (0.0246 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 100 ml of CH2Cl2, 4.1 ml (0.0295 mol) of triethylamine were added thereto and a solution of 4.3 ml (0.0295 mol) of 3-cyclopentylacetyl chloride in 40 ml of CH2Cl2 was added dropwise thereto at 15° under argon. The mixture was stirred at room temperature for 1/2 hour, then poured into water and extracted with CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and NaCl solutions, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with n-hexane/ethyl acetate 3:1 there were obtained 6.50 g (84%) of pale yellow oily rac-cis-3-(cyclopentylacetyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:32])[CH:6]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[N:15][C:16]([NH2:31])=[C:17]([O:19][CH:20]([C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=3[Cl:30])[CH3:21])[CH:18]=2)[CH:10]=[N:9]1)[CH3:7].C1COCC1.CO>O>[NH2:31][C:16]1[N:15]=[CH:14][C:13]([C:11]2[CH:10]=[N:9][N:8]([CH:6]([CH3:7])[C:5]([OH:32])=[O:4])[CH:12]=2)=[CH:18][C:17]=1[O:19][CH:20]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[Cl:30])[CH3:21]
Reactant: COC(=O)C(C)n1cc(-c2cnc(N)c(OC(C)c3c(Cl)ccc(F)c3Cl)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1cc(-c2cnn(C(C)C(=O)O)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 104.7 %

Procedure:
A solution of LiOH (34 mg, 1.4 mmol) in water (0.4 mL) was added to a solution of 2-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propionic acid methyl ester (70 mg, 0.15 mmol) in a mixture THF (1.5 mL) and MeOH (0.4 mL). After stirring overnight, the reaction was partitioned between dichloromethane and half-saturated brine. A small amount of ethanol was added and the pH was adjusted to 7 with 1 M HCl. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4, filtered and concentrated by rotary evaporation to give 2-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-propionic acid (69 mg, 100%).