Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[C:22]([Br:24])[C:21]([O:25][CH3:26])=[C:20]([Br:27])[CH:19]=2)=[CH:9][C:8]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:30]([O:29][C:8]1[CH:9]=[C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[C:22]([Br:24])[C:21]([O:25][CH3:26])=[C:20]([Br:27])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(C)(=O)=O)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.148 g, 0.0013 mol) was added dropwise a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.712 g, 0.0013 mol) in 6 mL of pyridine. The reaction mixture was stirred overnight at room temperature, diluted with 10 mL of chloroform, washed with 1N HCl and 1N NaOH, dried over Na2SO4 and concentrated. A residue was crystallizedfrom ethyl acetate-hexanes mixture. Yield 0.635 g (78%).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[C:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:26])[CH2:24][NH2:25])[CH2:19][CH2:18]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.CC(C)(C)CI.[C:33](=O)([O-])[O-:34].[K+].[K+]>CN(C)C=O>[CH:13]1[C:9]2[CH:10]=[CH:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[C:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:26])[CH2:24][NH:25][CH:33]=[O:34])[CH2:21][CH2:22]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reactant: O=C([O-])[O-]
Agent: CC(C)(C)CI
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=CNCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
150 mg (0.406 mmol) of 2-[4-(5H -dibenzo[a,d][7]annulen-5-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride, 80.5 mg (0.406 mmol) of 2,2-dimethyl-1-iodopropane and 84.3 mg (0.610 mmol) of potassium carbonate were dissolved in 1 ml of N,N-dimethylformamide, and the obtained solution was stirred at 120° C. overnight. The product was purified by the silica gel chromatography (hexane: ethyl acetate=9:1 to 2:3) to obtain the title compound.
Reaction SMILES: C(O[C:6](=[O:34])[NH:7][C@H:8]([C:13](=[O:33])[NH:14][C@H:15]([B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:31])[CH3:30])[O:21]1)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[C:35]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][C@@H:42]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=2)C(O)=O)[CH:36]=1>>[CH3:18][CH:17]([CH3:19])[CH2:16][C@H:15]([NH:14][C:13](=[O:33])[C@@H:8]([NH:7][C:6](=[O:34])[C@@H:42]([NH:41][C:37]1[CH:36]=[C:35]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:40]=[CH:39][CH:38]=1)[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[C:49]([O:55][CH3:56])[CH:48]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])[B:20]1[O:28][C@H:27]2[C@:22]([CH3:32])([C@H:23]3[CH2:29][C@@H:25]([CH2:26]2)[C:24]3([CH3:30])[CH3:31])[O:21]1
Reactant: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc1OC
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Product: COc1ccc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)cc1OC

Procedure:
The title compound is prepared as described in example 1 but using {(S)-3-Methyl-1-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butylcarbamoyl]-butyl}-carbamic acid tert-butyl ester and (S)-2-(Biphenyl-3-ylamino)-3-(3,4-dimethoxy-phenyl)-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[NH:4][C:5]1[C:6]([NH2:30])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=3)[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:13]=2)=[N:9][C:10]=1[NH2:11].[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O.O>C1COCC1>[CH3:1][O:2][C:3](=[O:31])[N:4]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=3)[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:13]=2)=[N:7][C:6]=1[NH2:30])[CH2:40][C:41]([F:44])([F:43])[F:42]
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: COC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(CC(F)(F)F)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1N
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A quantity of 3.470 g (8.138 mmol) of the compound from Example 1 was suspended in 35 ml of THF, admixed at 0° C. with 358 mg (8.952 mmol) of sodium hydride (60% suspension in mineral oil) and stirred at 0° C. for 90 min, in the course of which a solution was formed. A quantity of 2.519 g (8.952 mmol) of 2,2,2-trifluoroethyl trichloromethanesulphonate was added and the mixture was stirred at RT for 48 h. It was then stirred with water and concentrated on a rotary evaporator. The residue was taken up in ethyl acetate, and the organic phase was washed twice with water and dried over sodium sulphate. This gave 5.005 g of the target compound (79% of theory, purity by HPLC 65%). A quantity of 250 mg of the residue was purified by means of preparative HPLC (mobile phase: methanol/water, gradient 30:70→90:10).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:27]1([C:25]([N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:15][CH2:16]2)=[O:26])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2N)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 39 %

Procedure:
To a solution of 0.22 g of the compound of example 27 and 0.08 mL of triethylamine (TEA) in 5 mL of CH2Cl2, stirred at r.t. under anhydrous nitrogen atmosphere, was added dropwise a solution of 0.04 mL of methanesulphonyl chloride in 0.5 mL of CH2Cl2. The solution was stirred for 6 h at room temperature, afterwards, it was evaporated to dryness in vacuo and the residue was purified by flash chromatography (CH2Cl2-MeCN 9:1) affording 0.10 g (39%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:30][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]=3[C:41]([OH:43])=O)[C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:53][OH:54].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.C1COCC1.O.C(OCC)(=O)C>[OH:54][NH:53][C:41]([C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[CH:40][C:31]=1[CH2:30][N:19]([S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:44])[F:45])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)(=[O:17])=[O:18])[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])=[O:43]
Reactant: O=C(O)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Reactant: NO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NO)c1c(CN(C(=O)OCc2ccccc2)S(=O)(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To an ice cold solution of Example 9G (1.096 g, 1.72 mmol) in CH2Cl2 (12 mL) under N2 was added DMF (5 drops) and oxalyl chloride (0.30 mL, 3.45 mmol), and the reaction was allowed to stir at room temperature for 1 hour. The solvent was then removed by rotary evaporation chasing with anhydrous toluene (5 mL), and the residue was taken up in CH2Cl2 (7 mL) and added to a 0° C. solution of hydroxylamine hydrochloride (1.21 g, 0.017 mol) and triethylamine (2.9 mL, 0.021 mol) in THF/H20 (2:1 v/v, 12 mL). After allowing the reaction mixture to stir at room temperature for 3 hours, ethyl acetate (100 mL) and H2O (25 mL) were added, the layers were separated, and the organic phase was washed with 1 M HCl (2×10 mL), saturated aqueous NaHCO3 (10 mL), brine, dried (Na2SO4), filtered, and concentrated. The residue was triturated with CH2Cl2 (75 mL) and vacuum filtered to remove a solid impurity. The filtrate was concentrated and the residue purified on silica gel (1.9×6 cm) with a gradient of CH2Cl2 to 3% MeOH/CH2Cl2 +0.5% concentrated NH4OH to obtain 0.459 g (410%) of the desired compound as light beige solid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11]([OH:13])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][C:34]([CH3:39])([CH3:38])[CH2:35][CH2:36][NH2:37].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:33][C:34]([CH3:39])([CH3:38])[CH2:35][CH2:36][NH:37][C:11](=[O:13])[CH2:10][C:9]1[C:8]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=2[O:6][C:5]=1[C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21]
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CC(C)(C)CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)NCCC(C)(C)C)c2c1
Temperature: 45 °C

Procedure:
To a mixture of 29 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1, 23 mg HOBt, and 38.3 mg EDC was added 1 mL dry DMF. Add 24.9 mg (3,3-dimethylbutyl)amine hydrochloride followed by 61 μL DIEA. This solution was heated at 45° C. for 2 hours. It was purified directly on RP-HPLC using 60-75% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.08 min. (m/Z=290.1, 374.2, 396.2).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5]([F:8])=[N:6][CH:7]=1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH2:48][B-](F)(F)F)[C@@H:44]([CH3:53])[CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C(O[Pd]OC(=O)C)(=O)C>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[CH:3]=[C:2]([CH2:48][N:45]4[CH2:46][CH2:47][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:43][C@@H:44]4[CH3:53])[CH:7]=[N:6][C:5]=3[F:8])[N:10]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)n2)cc1
Temperature: 80 °C
Yield: 84.4 %

Procedure:
A mixture of 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (8.99 g, 18.73 mmol), potassium (S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate (6.00 g, 18.73 mmol), diacetoxypalladium (0.210 g, 0.937 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.893 g, 1.873 mmol), and cesium carbonate (18.31 g, 56.2 mmol) in THF (100 mL) and water (10.0 mL) was heated at 80° C. overnight. After cooling to ambient temperature, the mixture was passed through a short plug of Celite® (diatomaceous earth), washing with EtOAc (3×30 mL). The combined organic filtrates were concentrated and purified by flash chromatography (silica gel, 5% to 50% ethyl acetate/hexanes) to give (S)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (10.39 g, 15.80 mmol, 84% yield) as a pale-yellow foam. m/z (ESI, +ve ion) 658 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.Cl>[Cl-].[Zn+2].[Cl-]>[NH2:16][C:15]1[CH:17]=[CH:18][C:12]([F:11])=[CH:13][C:14]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])=[O:5]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: Nc1ccc(F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Nc1ccc(F)cc1C(=O)c1ccccc1Br
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 20 g (0.15 mol) of zinc chloride and 50 g (0.23 mol) of 2-bromobenzoyl chloride was heated to 110° C. 4-Fluoroaniline, 13 g (0.12 mol) Was added over a period of 2 minutes, raising the temperature of the mixture to 160° C. This mixture was then heated and stirred for 3 hours at 210°-220° C. After cooling to 140° C., 200 mL of hot 3N hydrochloric acid was added cautiously. The mixture was stirred and heated to reflux for 5 minutes and the aqueous phase was decanted from the residue. This procedure was repeated twice. The residue was dissolved in 200 mL acetic acid and treated with 100 mL of 3N hydrochloric acid and 10 mL of concentrated sulfuric acid to form a mixture.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(#N)C>[Br:12][C:8]1[CH:7]=[C:6]([C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH3:5])[CH2:3][OH:4])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: CC(N)(CO)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(CO)(NC(=O)CCl)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of crude (RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol (8.38 g, 36 mmol) and triethylamine (6.08 ml, 44 mmol) in acetonitrile (140 ml) was treated dropwise at −2° C. with chloroacetylchloride (3.25 ml, 40 mmol). After complete addition, the orange colored solution was left to warm to room temperature and stirring was continued for 2 h. For the workup, to the reaction was added silica gel (10 g) and it was evaporated at reduced pressure, thereafter, it was purified by chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 90/10 as the eluent. There were obtained 9.62 g (86% of theory) of (RS)-N-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide as a light brown oil. Mass (calculated) C11H13BrClNO2 [306.589]; (found) [M+H]+=306, [M+2-H]+=308.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:17][N:16](C(OCC4C=CC=CC=4)=O)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1>CCO.[Pd]>[NH:16]1[CH2:15][CH:14]([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][N:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:6][CH2:7]2)=[O:13])[CH2:17]1
Reactant: O=C(OCc1ccccc1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reaction time: 16 h
Yield: 92.5 %

Procedure:
To a solution of benzyl 3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidine-1-carboxylate (420 mg, 1.13 mmol) in EtOH (10 ml) was added 5% Pd—C (42 mg, 10% wt/wt). The flask was evacuated and the vacuum purged with N2 gas. The flask was evacuated again and the vacuum purged with H2 gas. The reaction was complete after 16 h, as shown by 1H NMR. The suspension was filtered through Celite® with MeOH washings (3×5 ml), and the combined filtrate dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (248 mg, 93% yield) as a viscous pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=O)[CH:7]=[CH:6]2.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]=[C:6]2[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cc2c(cc1OC)C(=O)C=C2
Reactant: C1CCNC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1OC)C(N1CCCC1)=CC2
Temperature: 25 °C
Yield: 45.6 %

Procedure:
5,6-Dimethoxy-1-indenone (5.1 g, 26.53 mmol) was dissolved in 120 mL of toluene. To this solution 17.7 mL (212 mmol) of pyrrolidine was added followed by 0.5 g of P2O5. The reaction mixture was refluxed for about 20 hours in a flask equipped with a Dean-Stark adapter. The flask was cooled to room temperature and the solvent was evaporated in vacuum leaving a brown-red solid. This solid was extracted with 50 mL of ether and filtered. The ether was evaporated leaving a brown solid. This solid was extracted with 120 mL of hot hexane and filtered. The hexane was removed and solid was dissolved in a mixture of 30 mL of toluene and 60 mL of hexane and filtered. The red solution was cooled to −27° C. overnight. The resulting solid was recovered by decantation, washed with cold hexane and dried under reduced pressure to give 2.97 g of 1-(5,6-dimethoxy-1H-inden-3-yl)pyrrolidine. Yield was 46 percent.
Reaction SMILES: Br[C:2]1[C:3]([NH2:20])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.F[B-](F)(F)[CH:23]=[CH2:24].[K+]>C(O)CC.Cl[Pd]Cl.[Fe]>[CH:17]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:2]([CH:23]=[CH2:24])[C:3]([NH2:20])=[N:4][CH:5]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15])([CH3:19])[CH3:18]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [K+]
Solvent: CCCO
Product: C=Cc1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N

Procedure:
dichloropalladium; iron (155.6 mg, 0.2132 mmol) was added to a solution of 3-bromo-5-(4-isopropylsulfonylphenyl)pyrazin-2-amine (455.6 mg, 1.279 mmol), TEA (323.6 mg, 445.7 μL, 3.198 mmol) and potassium trifluoro(vinyl)boranuide (171.3 mg, 1.279 mmol) in propanol (2 mL). The reaction mixture was heated in a microwave for 40 min at 100 C. The reaction mixture was concentrated in vacuo. The residue was partitioned between DCM and water. The organic extract was dried over MgSO4 and concentrated in vacuo yielding an oil that was purified by chromatography on silica using 100% DCM to DCM/MeOH 90/10 as elaunt to yield 5-(4-(isopropylsulfonyl)phenyl)-3-vinylpyrazin-2-amine as an orange solid. LC/MS m/z 304.3 [M+1]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[N:20]1[C:21]([C:29](O)=[O:30])=[CH:22][N:23]2[CH:28]=[CH:27][CH:26]=[N:25][C:24]=12.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:29]([C:21]3[N:20]=[C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:23]4[CH:22]=3)=[O:30])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1cn2cccnc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1cn2cccnc2n1

Procedure:
The title compound was prepared using the method of Example 34(d) from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), imidazo[1,2-a]pyrimidine-2-carboxylic acid (0.17 g, 1.07 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) using DMF (10 mL) as solvent. Yield 0.29 g. 1H NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 4.30 (dd, 1H), 4.49 (dd, 1H), 4.65 (m, 1H), 6.81 (dd, 1H), 6.98 (dd, 1H), 7.53 (d, 1H), 7.73 (dd, 1H), 8.08 (s, 1H), 8.48 (dd, 1H), 8.67 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][C:5]=3[C:4]=2[CH:3]=1.[CH2:29]([O:31][C:32](Cl)=[O:33])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: NCCCCCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCCCCCN1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1

Procedure:
Following the procedure of the preceding Example, 8-fluoro-5-(4-fluorophenyl)-2-(6-amino-1-hexyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.6 g, 4.2 mmoles) was reacted with ethylchloroformate (0.45 ml, 4.6 moles) in methylene chloride (5 ml) in the presence of triethylamine (2.3 ml, 16.7 mmoles), and the title product isolated and purified, except that ethyl acetate was used as eluant in the silica gel chromatography (365 mg, m.p. 159°-162° C.).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[CH:13]=2)[NH:8][CH:7]=1)[CH3:2].[CH3:31][C:32](C)([O-])C.[K+].C(I)C.O>CS(C)=O>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]([CH2:31][CH3:32])[S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)(=[O:17])=[O:18])[CH:13]=2)[NH:8][CH:7]=1)[CH3:30]
Reactant: CCN(CC)CCc1c[nH]c2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)CCc1c[nH]c2ccc(N(CC)S(=O)(=O)c3ccc4ccccc4c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 285 mg (0.7 mMol) of N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]naphthalene-2-sulphonamide (example 17) and 80 mg (0.7 mMol) of potassium t-butoxide in 3 ml of DMSO are stirred for 30 minutes at ambient temperature. Then are added 105 mg (0.7 mMol) of ethyl iodide and left with stirring for 3 hours. Water is added and is extracted with ethyl acetate. The organic solution is evaporated to dryness and the resulting crude is purified by chromatography on silica gel, using as an eluent mixtures of methylene chloride/methanol/ammonia, yielding N-[3-(2-diethylaminoethyl)-1H-indol-5-yl]-N-ethyl-naphthalene-2-sulphonamide as a solid with m.p.=49–50° C.