Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]([CH2:15][C:16]2([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[OH:22][C:16]1([CH2:15][C@H:5]2[CH2:4][CH2:3][C@H:2]([O:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:7][N:6]2[C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(O)CCC1CC1(O)CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Yield: 28.1 %

Procedure:
To a stirred solution of tert-butyl 5-hydroxy-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (1.92 g, 6.09 mmol, step 2 of Example 2), triethylamine (739 mg, 7.30 mmol) in dichloromethane (27 mL) was added methanesulfonyl chloride (836 mg, 7.30 mmol) at 0° C., and the mixture was allowed to warm to room temperature over 20 h. The mixture was quenched with water (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1:5) to give 673 mg (28%) of the title compound as a white crystal. (cis isomer, 634 mg, 26% yield)
Reaction SMILES: C(O)C.[OH-].[Na+].C([O:8][C:9]([CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)=[O:10])C>O>[C:9]([CH:11]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)([OH:10])=[O:8]
Reactant: CCOC(=O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Nc1ncnc2ccc(Cl)cc12)c1ccc2c(c1)OCO2
Yield: 48.5 %

Procedure:
10 ml of ethanol, 5 ml of water and 20 mg of sodium hydroxide were added to 100 mg of 4-(α-ethoxycarbonyl-3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 10 minutes and concentrated under a reduced pressure, followed by the addition of 20 ml of water. The obtained mixture was neutralized with 1N hydrochloric acid. The crystal thus precipitated was recovered by filtration. Thus, 45 mg of the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O.COCCOC>C(O)C>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]2[CH:13]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CCl)CCl
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc2nc(CCl)cn2c1
Reaction time: 2.75 h
Yield: 17.9 %

Procedure:
A mixture of 2-amino-5-picoline (Aldrich; 5.028 g), 1,3-dichloroacetone (Aldrich; 5.893 g), and 1,2-dimethoxyethane (Aldrich; 43 mL) is stirred for 1 h at 55° C., at which time ethanol (47 mL) is added and the mixture is stirred for 2.75 h at reflux. The mixture is then concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (1/99) and the appropriate fractions are combined and concentrated to give, after crystallization from ethyl acetate, 0.411 g of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine. Methanol is added to the filtrate, which is then concentrated to a reduced volume. The addition of hexane gives an additional 1.50 g of 2-(chloromethyl)-6-methylimidazo[1,2-a]pyridine in two crops; mp 88-89.25° C.; ms m/z 180; IR (mineral oil) 796, 705, 699, 1343, 1510 cm-1 ; 1H NMR (CDCl3) δ 2.32, 4.76, 7.03, 7.47, 7.53, 7.86.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[N:13]=[C:14]([C:22]#[CH:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[N:28]=[CH:29][S:30][CH:31]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9](=[O:10])[NH:11][C:12]1[N:13]=[C:14]([C:22]#[C:23][C:27]2[N:28]=[CH:29][S:30][CH:31]=2)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1nc(NC(=O)C(C)NC(=O)OC(C)(C)C)cc2ccccc12
Reactant: Brc1cscn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#Cc2cscn2)n1

Procedure:
A mixture of tert-butyl-N-[1-[(1-ethynylisoquinolin-3-yl)amino]-1-oxopropan-2-yl]-carbamate D4a (50 mg, 0.15 mmol), 4-bromo-1,3-thiazole (24 mg, 0.15 mmol), copper(I) iodide (3 mg, 0.02 mmol), Dichlorobis(triphenylphosphine)palladium(II) (10 mg, 0.01 mmol) and DIPEA (75 μl, 0.44 mmol) is stirred under argon atmosphere in NMP (1 ml) for 2 h at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 12 mg (19%). HPLC-MS: M+H=423; tR=1.84 min (*Method—4).
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[OH:16])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[OH:16])=[O:8])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1S,2S)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-chlorophenylboronic acid as starting materials, MS (ISP) 497.1 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3](=[O:20])[CH:2]([NH:1][C:29]([O:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:30])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1C(=O)C(N)N=C(C2CCCCC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.6 %

Procedure:
A solution of 3(R,S)-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.0 g) in anhydrous tetrahydrofuran (20 ml) under an atmosphere of nitrogen at 0° C. was treated with triethylamine (0.51 ml), followed by a solution of 4-nitrophenyl chloroformate (0.75 g) in anhydrous tetrahydrofuran (10 ml) dropwise. After stirring at ambient temperature for 20 min, the solid which precipitated from the mixture was filtered and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether to give the title compound (1.2 g, 75%) as a colourless solid. Mp 165°-168° C. 1H NMR (360 MHz, CDCl3) δ 1.05 (1H, m), 1.18-1.42 (3H, m), 1.55 (1H, m), 1.65 (3H, m), 1.87 (1H, m), 2.05 (1H, m), 2.80 (1H, m), 3.43 (3H, s), 5.18 (1H, d, J=8.3 Hz), 6.90 (1H, d, J=8.2 Hz), 7.30 (4H, m), 7.57 (2H, m), 8.23 (2H, d, J=7.1 Hz).
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[O-:20].[Na+]>>[C:1]1([S:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)(=[O:20])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-]Cl
Reactant: O=C(O)c1ccc(S(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
4-Benzenesulfinyl-benzoic acid (0.14 g, 0.5 mmol) was suspended in sodium hypochlorite solution (10 mL) and the reaction mixture stirred for 24 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was acidified with an aq. solution of 10% HCl solution. The resulting precipitate was filtered and washed with water. The residue was then redissolved in methanol and concentrated to get the title compound (0.105 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:6]([NH2:21])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[N:9][C:10]=1[NH2:11].CS(O[CH2:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[NH:4][C:5]1[C:10]([NH2:11])=[N:9][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:28][CH:29]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[N:13]=2)=[N:7][C:6]=1[NH2:21]
Reactant: COC(=O)Nc1c(N)nc(-c2n[nH]c3ncccc23)nc1N
Reactant: CS(=O)(=O)OCC1CCCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1c(N)nc(-c2nn(CC3CCCCCC3)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (1.0 mmol) of the compound of Example 1A and 224 mg (1.1 mmol) of cycloheptylmethyl methansulfonate (preparation: see J. Med. Chem. 2000, 43(26), 5017-5029) were initially charged in 5 ml of dimethylformamide, 354 mg (1.1 mmol) of cesium carbonate were added and the resulting mixture was stirred at RT overnight. 0.5 ml of 1N hydrochloric acid was added, and the entire solution was separated by HPLC (Method 5). The appropriate fractions were concentrated on a rotary evaporator, and the residue was dried under high vacuum. This gave 2.8 mg (0.7% of theory) of the target compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1.[OH-].[Na+:21].C(O)C>O>[Na+:21].[Na+:21].[NH2:1][C:2]1[C:11]2[C:10]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([S:16]([O-:19])(=[O:18])=[O:17])=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12

Procedure:
A 14.0 g amount of 4-amino-1,5-naphthalenedisulfonic acid is suspended in 100 ml of water and the solution is made basic with 5N sodium hydroxide. The solution is warmed and absolute ethyl alcohol is added until a solid is precipitated. The solid is collected by filtration and is washed with 85% aqueous ethyl alcohol, ethyl alcohol and ether, then dried in vacuo to yield 12.0 g of 4-amino-1,5-naphthalenedisulfonic acid disodium salt.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+]>C(O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CNC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1

Procedure:
A mixture of 26.4 g. of ethyl N-[4-(16-bromohexadecylamino)benzoyl]glycinate, 110 ml. of 1 N sodium hydroxide solution; and 100 ml. of ethanol is stirred at ambient temperature for 2 hours and then partially evaporated. The aqueous solution is washed with diethyl ether, acidified with 6 N hydrochloric acid, and filtered. The white solid is dried in vacuo and recrystallized from acetone to yield the product.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].[CH2:18](O)CCCC#C>>[CH2:8]([O:7][C:5]([NH:4][C@H:3]([C:13]([OH:15])=[O:14])[C:2]([CH3:17])([CH3:16])[CH3:1])=[O:6])[CH2:9][CH2:10][CH2:11][C:12]#[CH:18]
Reactant: C#CCCCCO
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Product: C#CCCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
N-[(Hex-5-yn-1-yloxy)carbonyl]-3-methyl-L-valine was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine by using hex-5-yn-1-ol instead of 4-pentenol. LRMS (ESI) m/z 256.2 [(M+H)+; calcd for C13H22NO4: 256.1].
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[CH:30][CH:29]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:35]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:33][CH:32]=4)=[S:36])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: CN(C)CCN1C(=O)c2cccc3cc4cccc(NC(=S)Nc5ccc(C(F)(F)F)cc5)c4c(c23)C1=O
Temperature: 25 °C
Yield: 90.1 %

Procedure:
200 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.60 mmole) were dissolved in 10 ml of acetonitrile. 244 mg (2 molar equivalents) of 4-(trifluoromethyl)phenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 290 mg of the desired product (formula shown hereinabove) were isolated as a red powder (yield=90%) which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: NCC(c1ccc(Cl)cc1)N1CCOCC1
Product: Cc1cccc(C(=O)NCC(c2ccc(Cl)cc2)N2CCOCC2)c1Cl

Procedure:
From 2-chloro-3-methylbenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:21][O:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:24](=[O:25])[CH2:23][O:22][CH3:21])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: COCC(=O)Cl
Reactant: Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12
Product: COCC(=O)Nc1c(C(=O)c2cccc(Cl)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-chlorobenzoyl)indole (Example 30) and methoxyacetyl chloride. m.p.: 154-155° C. 1H-NMR (CDCl3) δ: 10.22 (1H, br s), 8.41 (1H, br s), 8.21 (1H, d, J=9.2 Hz), 7.77 (1H, dd, J=1.5, 2.2 Hz), 7.68 (1H, ddd, J=1.1, 1.5, 7.7 Hz), 7.59 (1H, ddd, J=1.1, 1.8, 7.7 Hz), 7.49 (1H, dd, J=7.7, 8.1 Hz), 7.34 (1H, d, J=1.8 Hz), 7.13 (1H, dd, J=1.8, 8.8 Hz), 4.05 (2H, s), 3.53 (3H, s)
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=2)=[O:27])[CH2:22][CH2:21]1.C=O>C(#N)C>[N:19]1([CH:20]2[CH2:21][CH2:22][N:23]([C:26]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:29]=3)=[O:27])[CH2:24][CH2:25]2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[CH:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCc1ccc(C(=O)N2CCC(Nc3ccccc3N)CC2)cc1
Agent: C=O
Solvent: CC#N
Product: CCCCc1ccc(C(=O)N2CCC(n3cnc4ccccc43)CC2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
p-Toluenesulfonic acid (catalytic amount) was added to a solution of [4-(2-amino-phenylamino)-piperidin-1-yl]-(4-butyl-phenyl)-methanone (50 mg, 0.142 mmol) and paraformaldehyde (500 mg) in acetonitrile (10 mL). The reaction was heated at 80° C. for 4 h. The reaction mixture was concentrated and the crude product was purified by column chromatography on silica gel using chloroform/methanol/ammonia (96:3.6:0.4) as the eluent. The product fractions were combined and evaporated to give (4-benzoimidazol-1-yl-piperidin-1-yl)-(4-butyl-phenyl)-methanone (39 mg, 76%) as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.S(OC)(O[CH3:15])(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:15])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: Brc1cccc2cn[nH]c12
Solvent: Cc1ccccc1
Product: Cn1cc2cccc(Br)c2n1
Yield: 72.7 %

Procedure:
A solution of 7-bromo-1H-indazole (3; 1.71 g, 8.67 mmol) and dimethyl sulfate (0.90 mL, 9.5 mmol) in 30 mL of toluene was stirred at 110° C. for 4 h, then allowed to cool. The mixture was carefully washed with 30 mL of a saturated aqueous NaHCO3 solution, dried over MgSO4, filtered (rinsing with diethyl ether), and concentrated to an orange oil Column chromatography (0→50% EtOAc/hexanes) afforded 7-bromo-2-methyl-2H-indazole (6: R=Me; 1.33 g, 73%) as a light tan solid.
Reaction SMILES: CN(C)C1N=CC([C:9]2[N:10]=[C:11]([CH2:36][CH3:37])[C:12]([NH:17][C@H:18]3[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:19]3)=[N:13][C:14]=2[CH2:15][CH3:16])=C(C)C=1.[CH3:40][O:41][C:42]1[N:47]=[C:46]([CH3:48])[C:45](B(O)O)=[CH:44][CH:43]=1>>[CH2:36]([C:11]1[C:12]([NH:17][C@H:18]2[C@@H:22]([O:23][CH2:24][CH3:25])[CH2:21][N:20]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:19]2)=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:45]2[C:46]([CH3:48])=[N:47][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)[N:10]=1)[CH3:37]
Reactant: COc1ccc(B(O)O)c(C)n1
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2cnc(N(C)C)cc2C)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC

Procedure:
Following the procedure for the preparation of benzyl (3R,4S)-3-({5-[6-(dimethylamino)-4-methylpyridin-3-yl]-3,6-diethylpyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate but substituting 6-methoxy-2-methylpyridin-3-ylboronic acid provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.41–7.36, 6.64, 5.17–5.15, 4.78, 4.11, 4.02–3.97, 3.73–3.35, 2.70, 2.46, 2.28, 1.32–1.21, 1.13; IR (liq.) 2236 (w), 2018 (w), 1949 (w), 1709 (s), 1596, 1565, 1499, 1474 (s), 1420 (s), 1396, 1360, 1350, 1304 (s), 1126, 1097 cm−1 HRMS (ESI) calcd for C29H37N5O4+H1 520.2924. found 520.2924.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:34])[C:24]=1[N:25]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[N:26]1)[O:5][CH:6]([CH:16]1[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[NH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([CH3:34])[C:24]=1[N:25]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[N:26]1)[O:5][CH:6]([CH:16]1[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCN
Reactant: Cc1cc(OC(c2ccc(C(=O)O)cc2)C2CC(C)(C)C2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1ccc(C(Oc2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CC(C)(C)C2)cc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
Tetrahydrofuran (1.2 mL) was added to a vial containing 4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoic acid (115 mg, 0.240 mmol), ethyl 3-aminopropanoate hydrochloride (74.7 mg, 0.490 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (185 mg, 0.490 mmol). Diisopropylethylamine (0.210 mL, 1.22 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded ethyl 3-(4-((3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoate (110 mg, 39% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.71 (d, J=8.6 Hz, 2H), 7.64 (s, 1H), 7.36 (d, J=8.2 Hz, 2H), 6.81 (t, J=4.8 Hz, 1H), 6.57 (s, 2H), 5.00 (d, J=6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.71 (q, J=6.1 Hz, 2H), 2.57-2.74 (m, 3H), 1.87-1.92 (m, 7H), 1.80-1.87 (m, 1H), 1.72-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.21-1.35 (m, 3H), 1.13 (s, 3H), 1.10 (s, 3H). MS (M+1): 572.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH:30][S:31]([C:34]2[S:35][C:36](Br)=[CH:37][CH:38]=2)(=[O:33])=[O:32])=[CH:24][CH:23]=1>>[N:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][S:31]([C:34]2[S:35][C:36]([C:21]#[C:20][C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]5[CH2:16][CH2:15]5)=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[CH:37][CH:38]=2)(=[O:33])=[O:32])=[CH:26][CH:27]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: O=S(=O)(NCCc1ccncc1)c1ccc(Br)s1
Product: O=S(=O)(NCCc1ccncc1)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (147 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2-pyridin-4-yl-ethyl)-amide (example B.60) (174 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (112 mg, 40%). MS (ISP) 560.2 [(M+H)+]; mp 172-174° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)(=[O:20])[CH3:19]
Reactant: Oc1ccc2ncccc2c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of quinolin-6-ol (4.5 g, 31.0 mmol) and pyridine (3.01 ml, 37.2 mmol) in DCM (50 ml) was added acetyl chloride (2.65 ml, 37.2 mmol) at 0° C. The mixture was then stirred at rt for 8 h. The reaction was quenched with saturated NaHCO3 and the mixture was extracted with DCM (30 ml) three times. The combined organic phase was washed with brine and dried over anhydrous MgSO4, filtered and concentrated to give the title compound (5.0 g, 68.9% yield), which was used directly in next step. LCMS (method B): [M+H]+=188, tR=1.64 min.