Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]12[CH2:10][C:7]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)=O.[C:20]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([C:3]12[CH2:10][C:7]([NH:11][C:12]([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)=[O:13])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)#[CH:20]
Reactant: O=CC12CCCC(NC(=O)c3cnccn3)(CC1)C2
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC12CCCC(NC(=O)c3cnccn3)(CC1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a stirred mixture of N-(5-formylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide (350 mg, 1.35 mmol) and K2CO3 (370 mg, 2.7 mmol) in methanol (25 mL) under N2 was added dimethyl (1-diazo-2-oxopropyl)phosphonate (310 mg, 1.62 mmol). After stirring at room temperature for three hours, the clear reaction solution was partitioned between ethyl acetate (20 mL) and 5% NaHCO3 (20 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 210 mg (61%) of crude title compound, N-(5-ethynylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide, as an off-white solid. ESI-MS m/z: 256 (M+H)+. It was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13]C#N)=[CH:11][CH:10]=[C:9]2[CH:16]=[O:17])=[N:4][CH:5]=[CH:6][CH:7]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([SH:13])=[CH:11][CH:10]=[C:9]2[CH:16]=[O:17])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CSc1ccc(C=O)n1-c1ncccc1Cl
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CC(=O)O
Product: O=Cc1ccc(S)n1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A mixture of 0.70 g of 1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrole-2-carbaldehyde, 0.64 g of sodium sulfide nonahydrate and 10 ml of water was stirred for 1 hour under heat refluxing. The reaction mixture was allowed to cool to room temperature, adjusted to pH 5 by an addition of acetic acid, and then extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with methyl tert-butyl ether to obtain 0.50 g of 1-(3-chloro-2-pyridinyl)-5-mercapto-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Br:1][C:2]1[C:7]2[C@H:8]([CH3:13])[CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:14].[CH3:15]N1C[C@H](C)C2C(Cl)=C(Cl)C=CC=2CC1>>[CH3:15][N:10]1[CH2:9][C@@H:8]([CH3:13])[C:7]2[C:2]([Br:1])=[C:3]([Cl:14])[CH:4]=[CH:5][C:6]=2[CH2:12][CH2:11]1
Reactant: C[C@@H]1CNCCc2ccc(Cl)c(Br)c21
Reactant: C[C@H]1CN(C)CCc2ccc(Cl)c(Cl)c21
Product: C[C@@H]1CN(C)CCc2ccc(Cl)c(Br)c21

Procedure:
Compound 11 was prepared from (S)-9-bromo-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine utilizing a similar procedure as described herein for the preparation of Compound 9. 1H NMR (400 MHz, CDCl3) δ 7.18 (d, J=8 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 3.94-3.88 (m, 1H), 3.29 (ddd, J=15, 12, 2 Hz, 1H), 2.98-2.93 (m, 1H), 2.90 (ddd, J=15, 6, 1 Hz, 1H), 2.36-2.32 (m, 4H)2.13 (t, J=11 Hz, 1H), 1.33 (d, J=7 Hz, 3H). MS calculated for C12H15Cl2N+H: 288, observed: 288.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1.[CH3:22]I.[Cl-].[NH4+]>CN(C=O)C.CC(OC)(C)C>[CH3:22][CH:19]1[C:18](=[O:21])[CH2:17][CH2:16][C:15]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:20]1
Reactant: CI
Reactant: O=C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CC1CC2(CCC1=O)OCCO2
Temperature: -60 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of LHMDS (1.0 M in THF, 2.1 L, 2.1 mol) at −60° C. was added 1,4-dioxaspiro[4.5]decan-8-one (300 g, 1.9 mol) in DMF (1.2 L) slowly via an addition funnel while maintaining the reaction temperature below −60° C. The reaction mixture was allowed to stir at −60° C. for 1.5 h, and treated with MeI (286 g, 2.0 mol) via an addition funnel. The reaction mixture was allowed to warm to room temperature over 3 h, and treated with half-saturated ammonium chloride solution (2 L). The mixture was diluted with MTBE (2 L), washed with water (×3), dried (magnesium sulfate), and concentrated. The residue was azeotroped with isooctane (500 mL×2), and recrystallized from isooctane to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 4.05-3.95 (m, 4H); 2.70 (m, 1H); 2.61 (dtd, 1H); 2.33 (ddd, 1H); 2.10-1.97 (m, 2H); 1.92 (dt, 1H); 1.68 (t, 1H); 1.00 (d, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>O=S(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC(C)=O
Reactant: Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc(Cl)cc3)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 6-acetoxy-7-methoxy-quinazolin-4-one (RO0505111-000) (1.0 g, 4.26 mmol) (from Example 15, Step A, supra) in SOCl2 (12.5 mL) (Aldrich) was added a few drops of DMF (0.1 mL). The reaction mixture was then heated with stirring at 100° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (20 mL), then 4-chloroaniline (0.6 g, 4.69 mmol) (Fluka) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was collected and dried in vacuo to give 6-acetoxy-4-(4-chloro-phenylamino)-7-methoxy-quinazoline as a gray solid. (Yield 1.45 g, 99%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:22])([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:22][C:9]([O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)(Cc1ccc(OCCOC2CCCCO2)cc1)Oc1ccccc1
Yield: 72.4 %

Procedure:
In a similar manner to that described in Reference example 3(e), a reaction was carried out using ethyl 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionate (1.55 g), which is the product of Reference example 8(b), 2-(2-bromoethoxy)tetrahydropyran (1.08 g) and potassium carbonate (2.14 g) in dimethylacetamide and the reaction mixture was treated to afford the desired compound (1.60 g) as a syrup.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=O.[NH3:31]>>[NH2:31][C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)=[O:3]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(C(F)(F)F)n3)C2)cc1
Reactant: N
Product: CC(Cc1ccc(OCC(N)=O)cc1)N1CCOC(c2csc(C(F)(F)F)n2)C1

Procedure:
Prepared by analogy to Example 24 by reaction of N-[2(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholine with ammonia followed by purification on a silica gel column using ethyl acetate/toluene=8:2 as eluant.
Reaction SMILES: C(OC(=O)[C@@H](OC)CC1C=CC(OCC(O)=O)=CC=1)C.C(N)CCCCC.[CH2:28]([O:30][C@@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][C@@H:43]([C:45](=[O:62])[NH:46][CH2:47][CH2:48][C:49]2C=C[C:52](OC3C=CC=CC=3)=[CH:51][CH:50]=2)C)=[CH:38][CH:37]=1)[C:32]([OH:34])=[O:33])C>>[CH2:47]([NH:46][C:45]([CH2:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@H:31]([O:30][CH3:28])[C:32]([OH:34])=[O:33])=[CH:37][CH:38]=1)=[O:62])[CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Agent: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Solvent: CCCCCCN
Product: CCCCCCNC(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and hexylamine via the same procedure used for the preparation of (2S,1R)-2-Ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C18H27NO5 [M−H]−: 338.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[CH:10][N:11]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].ClCCl>[Cl:8][C:5]1[N:4]2[N:9]=[CH:10][N:11]=[C:3]2[C:2]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1ccc(Br)c2ncnn12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ccc(Cl)n4ncnc34)cc2)CC1
Yield: 64.4 %

Procedure:
A solution of 8-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine (100 mg, 0.43 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (91 mg, 0.47 mmol), sodium-tert-butoxide (58 mg, 0.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (39 mg, 40 μmol) and Xantphos (50 mg, 90 μmol) in dioxane is degassed for one minute by nitrogen bubbling and irradiated in a sealed tube in a microwave (CEM Explorer) under a nitrogen atmosphere for 45 minutes at 110° C. After addition of dichloromethane the suspension is filtered through a plug of silica and the filtrate evaporated and stripped twice with dichloromethane. The residue is purified by flash chromatography (silica gel, dichloromethane/7N NH3 in methanol 95:5) affording the title compound (95 mg) as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:18]([CH2:19][O:20][CH3:21])[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.C(OCl)(C)(C)C>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCc2[nH]c3cccc(Cc4ccccc4Cl)c3c2C1COC
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c2c1COC
Temperature: 25 °C
Yield: 33.6 %

Procedure:
1 g (0.0024 mol) of 1,2,3,4-tetrahydro-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is mixed in a mixture of 20 ml of toluene and 7 ml of dichloromethane at -15° C. with 1.2 ml of triethylamine. Then 0.9 ml (0.0074 mol) of tert.butylhypochlorite, dissolved in 12 ml of dichloromethane, is instilled. The reaction mixture is stirred at room temperature for two more hours. The evaporation residue is chromatographed on silica gel with equal parts of acetone and dichloromethane and yields 0.33 g (33% of theory) of 5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester, melting point 182°-184° C. (from ethanol).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([N:6]1[C:14]2[C:13]([O:15][CH3:16])=[CH:12][CH:11]=[C:10]([C:17]([O:19]C)=[O:18])[C:9]=2[CH:8]=[CH:7]1)[CH3:5]>C(O)C>[CH3:5][CH:4]([N:6]1[C:14]2[C:13]([O:15][CH3:16])=[CH:12][CH:11]=[C:10]([C:17]([OH:19])=[O:18])[C:9]=2[CH:8]=[CH:7]1)[CH3:3]
Reactant: COC(=O)c1ccc(OC)c2c1ccn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=O)O)c2ccn(C(C)C)c12
Yield: 92.7 %

Procedure:
Added 1 N sodium hydroxide (6.47 mL, 6.47 mmol) to a solution of methyl 1-(1-methylethyl)-7-(methyloxy)-1H-indole-4-carboxylate (400 mg, 1.618 mmol) in ethanol (30 mL) and heated at reflux for 3 h. The EtOH was removed in vacuo and the residue dissolved in 20 ml of water. Acidifed solution by addition of 1 N HCl and extracted with DCM. the combined DCM extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to give 350 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.51 (d, 6H), 4.03 (s, 3H), 5.47 (dt, J=13.39, 6.69 Hz, 2H), 6.70 (d, J=8.34 Hz, 2H), 7.23 (d, J=3.28 Hz, 2H), 7.37 (d, J=3.03 Hz, 2H), 7.99 (d, J=8.34 Hz, 2H). MS (ES) [M+H]+ 234.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[K+]>C(O)C>[F:14][C:11]([F:12])([F:13])[C:10]1[N:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnn(-c2ccc(Cl)cc2Cl)c1C(F)(F)F
Yield: 62.2 %

Procedure:
5-(Trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (3.31 grams, 0.0094 mole) and potassium hydroxide (0.8 gram, 0.014 mole) were combined in 25 ml. of ethanol. The reaction mixture was refluxed for 2 hours, then poured into 150 ml. of ice/water and filtered to remove solids. The remaining solution was acidified with concentrated HCl, filtered to separate the precipitate which was then dried and recrystallized from cyclohexane/toluene with charcoal, yielding 1.90 grams of 5-(trifluoromethyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, mp=154°-155° C.
Reaction SMILES: Br[C@@H:2]1[C@H:6]2[O:7][CH2:8][CH2:9][C@@:5]2([CH2:10][OH:11])[CH2:4][C@@H:3]1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CCOC(C)=O.[Pd]>[OH:11][CH2:10][C@:5]12[CH2:4][C@H:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:2][C@H:6]1[O:7][CH2:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@]2(CO)CCO[C@@H]2[C@H]1Br
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(CO)C1

Procedure:
A solution of the product of Step G (83 g, 0.245 mol), 10% Pd on C (12.5 g), triethylamine (69 mL, 0.49 mol, 2 eq.) in EtOAc (830 mL) was shaken on a PAAR hydrogenator at 40 psi for 3.5 h until the pressure remained constant. The reaction was filtered with celite, the filter cake was washed with EtOAc, and the collected filtrate was washed with aqueous HCl (1N), brine, dried (Na2SO4) and concentrated under reduced pressure to give the product of Step H. 1H NMR (400 MHz, CHLOROFORM-d) d=4.60-4.73 (m, 1H), 4.06-4.24 (m, 3H), 3.84-3.93 (m, 1H), 3.52-3.67 (m, 4H), 2.12-2.21 (m, 1H), 1.98-2.04 (m, 1H), 1.90 (br. s., 3H), 1.70-1.78 (m, 1H), 1.46-1.56 (m, 3H), 1.44 (s, 11H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O>CCO.Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([N:7]2[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]2[CH3:13])[CH:8]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: CC(=O)CCC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Br)cc1-n1c(C)ccc1C
Yield: 59.8 %

Procedure:
To a solution 5-bromo-2-methyl aniline (6.38 g, 36.74 mmol) in EtOH (30 ml) was added acetonyl acetone (5.0 ml, 42.62 mmol) and one drop of conc. aqueous HCl. The mixture was heated at reflux for 18 h and then cooled. Solvent was evaporated to dryness under reduced pressure and the residue was partitioned between water and EtOAc. The organic layer was separated and washed with water and brine dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/8:2) gave 5.8 g of 1-(5-bromo-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrole (60%) as a clear oil.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:34][C:35]3[C:36]([C:41]#[N:42])=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:21][CH2:22][N:23]3[CH:28]=[CH:27][C:26]4[O:29][C:30]([CH3:32])=[CH:31][C:25]=4[C:24]3=[O:33])[CH:17]=[CH:18][C:4]1=2)[CH3:2].C[C:44](C)=[O:45]>[Ni].C(O)=O>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:34][C:35]3[C:36]([CH2:41][NH:42][CH:44]=[O:45])=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:21][CH2:22][N:23]3[CH:28]=[CH:27][C:26]4[O:29][C:30]([CH3:32])=[CH:31][C:25]=4[C:24]3=[O:33])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3C#N)ccc21
Reactant: CC(C)=O
Agent: [Ni]
Solvent: O=CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3cccnc3CNC=O)ccc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
3-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)pyridine-2-carbonitrile(0.40 g) and Raney nickel(1.2 g) were suspended in formic acid(8 ml), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was filtered to remove insoluble matter, and the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol=75:25→80:20). The purified product was condensed under reduced pressure. Acetone and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound(33 mg) as a pale brown white amorphous.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].C(OC(=O)[NH:14][C@@H:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([C:27]2[CH:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=2)=[O:26])[C:19]=1[F:34])[CH2:16][CH3:17])(C)(C)C>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:15]([NH2:14])[CH2:16][CH3:17])=[C:19]([F:34])[C:20]=1[C:25]([C:27]1[CH:28]=[N:29][C:30]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:31][CH:32]=1)=[O:26]
Reactant: c1cn[nH]c1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(Cl)nc2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(-n3cccn3)nc2)c1F
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To Pyrazole (0.016 g, 0.23 mmol) in DMF (2 ml) added sodium hydride (60%) (0.01 g, 0.25 mmol) then stirred at ambient for 15 minutes. {(R)-1-[4-Chloro-3-(6-chloro-pyridine-3-carbonyl)-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester [from Example 1, step 1] (0.1 g, 0.23 mmol) in DMF (2 ml) added dropwise, stirred at ambient for 1 hour, reaction quenched using water and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated, MS: [M+H] 459. Residue treated with saturated HCl/EtOAc stirred at ambient for 1 hour. Mixture was concentrated, solid triturated with EtOAc, filtered and washed with EtOAC to give (1R)-1-(4-chloro-2-fluoro-3-{[6-(1H-pyrazol-1-yl)pyridin-3-yl]carbonyl}phenyl)propan-1-amine (0.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:27][C:28](OC)=[O:29])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=3)=[C:4]([CH2:32][NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:3]=1.CO[Na]>CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3=[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:14]=[CH:13][C:12]([C:23]([O:25][CH3:26])=[O:24])=[CH:11][C:10]=4[N:9]3[CH2:27][C:28](=[O:29])[N:33]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:32][C:4]=2[CH:3]=1
Reactant: COC(=O)Cn1c(-c2ccc(Cl)cc2CNCCN(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CO[Na]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1cc(Cl)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[4-chloro-2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl-3-cyclohexyl-1-(2-methoxy-2-oxoethyl)-1H-indole-6-carboxylate (from Step 5) in dry MeOH (0.05 M), 10% in weight of MeONa was added and the mixture stirred at RT overnight. The volume of the solution was reduced in vacuo before being diluted with EtOAc. The organic phase was washed with HCl 1 N, brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was then used in the next step without any further purification (quant); MS (ES+) m/z 508 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH2:10][C@@H:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=3[Cl:21])[NH:14][C@@H:13]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:23]([C@H:13]1[CH2:12][C@H:11]([CH2:10][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[CH:18][C:19]=2[Cl:21])[NH:14]1)([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H](CC(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21)Nc1ccccc1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
Trans-4-phenylaminocarbonylmethyl-2-tertiarybutyloxycarbonyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (0.12 g) was dissolved in 10% aqueous trifluoroacetic acid (30 ml) and stood at room temperature for 30 mins. The solvents were removed under vacuum and the residue chromatographed on silica gel using 3% methanol, 1% acetic acid, 96% dichloromethane to give a solid which was recrystallised from diethyl ether/hexane to give the title compound as a colourless solid (0.035 g, m.p. 208° C. dec); δ (360 MHz, DMSO) 1.62 (1H, ddd, J=13.0, 12.4 and 3.9 Hz, CHACHBHCCHD), 2.19 (1H, d, J=13.0 Hz, CHACHBHCCHD), 2.49 (2H, m, CHEHFCONHPh), 3.58 (1H, m, CHACHBHCCHD), 4.08 (1H, dd, J=12.4 and 3.4 Hz, CHACHBHCCHD), 6.62 (2H, m, 6-H or 8-H and NH), 6.80 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.04 (1H, t, J=7.4 Hz, p proton), 7.31 (2H, t, J=7.4 Hz, m protons), 7.59 (2H, d, J=7.4 Hz, o protons); m/e (FAB) 379 (M+1); Found C, 57.18; H, 4.31; N, 7.22. C18H16Cl2N2O3 requires C, 57.01; H, 4.25; N, 7.39%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17].C(N(CC)CC)C.O1CCCC1>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[C:16](=[O:17])[O:15][CH2:14][CH:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1CN(Cc2ccccc2)CCN1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCC2CN(Cc3ccccc3)CCN12
Yield: 64.6 %

Procedure:
A mixture of (4-benzylpiperazin-2-yl)methanol (2.8 g, 10 mmol) prepared according to J. Med. Chem. 1993, 36, 2075-2083 and 1,1′-carbonylbis(1H-imidazole) (3.2 g), triethylamine (2.8 ml) and tetrahydrofuran (30 ml) was stirred at 80° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.5 g, yield 65%) as a colorless oil from a fraction eluted with ethyl acetate. MS 233 (M+1).