Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([N:15]=C=O)([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:15])([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(N=C=O)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC1(N)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 812 mg (3.38 mmol) rac-3-isocyanato-3-methyl-piperidine-1-carboxylic acid tert-butyl ester in 17 ml THF were added 16.9 ml 2N NaOH and the emulsion stirred vigorously at ambient temperature for 20 h. The emulsion was diluted with tert-butyl methyl ether and extracted three times. The combined extracts were washed with brine to neutral pH, dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography on silica gel with a gradient of heptane and 10 to 100% ethyl acetate then with ethyl acetate/MeOH provided the title compound: 232 mg colourless oil which crystallized at ambient temperature MS (m/e): 215.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([NH2:10])=[C:4]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[CH:3]=1.[CH2:20]([O:22][C:23](=[O:30])[CH2:24][C:25](=O)[CH:26]([CH3:28])[CH3:27])[CH3:21]>>[CH2:20]([O:22][C:23]([C:24]1[C:25]([CH:26]([CH3:28])[CH3:27])=[N:10][C:5]2[C:4]([C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[O:8][CH3:9])=[O:30])[CH3:21]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: COc1cc(Cl)cc(C#Cc2ccccc2Cl)c1N
Product: CCOC(=O)c1c(C(C)C)nc2c(OC)cc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 10 step B from 4-chloro-2-(2-chloro-phenylethynyl)-6-methoxy-phenylamine (200 mg, 0.68 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.166 ml, 1.03 mmol). Brown solid (45 mg, 15%). LC-MS (ESI): 432 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:47]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([F:40])([F:41])[F:42])[CH2:12][C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)=[CH:5][CH:4]=2)=[N:2][N:49]=[N:48]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2C(F)(F)F)CCc2ccc(C#N)cc2)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2C(F)(F)F)CCc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 212 mg (0.26 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-{[2-(trifluoromethyl)benzyl]oxy}phenyl)but-3-en-1-yl)benzoate in 3 ml of toluene is mixed with 450 mg (3.91 mmol) of trimethylsilyl azide and 97.3 mg (0.39 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by chromatography on a silica gel column (mobile phase: cyclohexane/ethyl acetate 1:1). 120 mg (0.19 mmol, 75% of theory) of a colorless foam are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[OH:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:34]=[CH:35][C:36]=1[OH:37]
Reactant: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(-c5ccc(O)c(Cl)c5)cc34)CC2)CC1
Yield: 57.9 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (30 mg, 0.065 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (26 mg, 0.150 mmol) to afford the desired product (19 mg, 57%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.28 (s, 1H), 8.06-7.98 (m, 2H), 7.71 (d, J=2.3 Hz, 1H), 7.54 (dd, J=8.4, 2.3 Hz, 1H), 7.09-7.03 (m, 1H), 3.55 (d, J=12.8 Hz, 2H), 3.34 (s, 3H), 3.23-3.15 (m, 2H), 2.81-2.50 (m, 8H), 2.35 (s, 3H), 2.12 (d, J=10.6 Hz, 2H), 1.92-1.81 (m, 2H), 1.34-1.28 (m, 2H), 1.27-1.20 (m, 2H); ESI MS m/z 505 [C29H33ClN4O4+H]+; HPLC>99% (AUC), tR=10.01 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(c2cc(F)cc(F)c2)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(c1cc(F)cc(F)c1)C1CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 360 mg (1.06 mmol) of tert-butyl 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidine-1-carboxylate in 1.5 mL of CH2Cl2, was added 1.5 mL of TFA and the solution was stirred for 1 h at rt. It was concentrated and washed with ether to afford the title compound as a white solid; Mass Spectrum: m/e=240 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=2[CH3:32])=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[CH2:35]([O:37][CH2:38]Cl)[CH3:36].Cl>O1CCCC1>[CH2:35]([O:37][CH2:38][N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:14]([F:17])([F:15])[F:16])[C:18]([F:20])([F:21])[F:19])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:28]([CH3:34])=[N:29][N:30]([CH3:33])[C:31]=1[CH3:32])=[O:26])[CH3:36]
Reactant: COC(c1ccc(NC(=O)c2c(C)nn(C)c2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCN(C(=O)c1c(C)nn(C)c1C)c1ccc(C(OC)(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Sodium hydride (29 mg, 60%, 0.73 mmol) was suspended in tetrahydrofuran (10 ml), and a solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-1,3,5-trimethylpyrazole-4-carboxamide (260 mg, 0.48 mmol) in tetrahydrofuran (5 ml) was added dropwise. After stirring at room temperature for 30 min, a solution of chloromethyl ethyl ether (70 mg, 0.73 mmol) in tetrahydrofuran (2 ml) was added, and the mixture was stirred for one day. The reaction mixture was poured into diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to give the desired compound (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]([C@H:36]1[CH2:41][CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1)[CH3:35])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([N:34]([CH3:35])[C@H:36]4[CH2:41][CH2:40][CH2:39][NH:38][CH2:37]4)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: CN([C@H]1CCCN(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1Br
Product: CN([C@H]1CCCNC1)S(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (S)-tert-butyl 3-(2-bromo-N-methylphenylsulfonamido)-piperidine-1-carboxylate yielding 41 mg (48%) of the title compound after HPLC purification. MS (ESI): mass calcd. for C27H32FN5O4S, 541.21; m/z found, 542.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][CH2:22][OH:23]>CN(C)C=O>[OH:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: COC(=O)C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OCCO)cc1
Yield: 43.1 %

Procedure:
30 g (168 mmol) of methyl 3-(4-hydroxyphenyl)-acrylate (Example 1), 29 g (210 mmol) of anhydrous K2CO3 and a spatula tip of KI were placed in 200 ml of dimethylformamide. 14.91 g (185 mmol) of 2-chloroethanol were added dropwise at 85° C. within 5 minutes while stirring. The batch was stirred at 85° C. for a further 3 days. Subsequently, the salts were filtered off and the filtrate was concentrated to dryness in a water-jet vacuum. 16.1 g of methyl (E)-3-[4-[2-hydroxyethoxy]-phenyl]-acrylate were obtained in the form of white crystals after recrystallization from i-propanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12.O[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:3]=12
Reactant: Fc1cccc(-c2n[nH]c3nnc(-c4ccccc4)c(Cl)c23)c1
Reactant: O=C1CCCN1CCO
Product: O=C1CCCN1CCn1nc(-c2cccc(F)c2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound IIr was synthesized from 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 1-(2-hydroxyethyl)pyrrolidin-2-one following the general procedure for the Mitsunobu reaction as described.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:10]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: O=C1CCCCCN1
Reactant: C=C(C)C(=O)Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)N1CCCCCC1=O

Procedure:
74 g of ε-caprolactam in 700 ml dry toluene is heated with 9.5 g of sodium at 90°-95° C. When all of the sodium metal has reacted, 43 ml of methacryloyl chloride in 50 ml dry benzene is added dropwise into the voluminous caprolactam salts at 4°-6° C. The mixture is then poured into a separatory funnel, washed with 200 ml water, 200 ml of sodium dicarbonate solution, and again with 20 ml water. The organic compounds are extracted with ether from the water phase, and the ether solution and benzene solution are dried over CaCl2 and the solvent evaporated under reduced pressure. The product, N-methacryloylcaprolactam, comes off at 90° C./2 mm hg. The yield is 32.3 g (42.8% based on sodium).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([O:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]([O:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[CH2:3][CH2:2]1
Reactant: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(Cc1ccc(OCCN2CCOc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
To a solution of methyl 3-[4-[2-(2,3-dihydro-1,4-benzoxazin-4-yl)ethoxy]phenyl]-2-ethoxy propanoate (4.7 g, 12.2 mmol) obtained in example 2 in methanol (50 mL) was added aqueous 10% sodium hydroxide (28 mL). The mixture was stirred at 25° C. for 3h. The solvent was removed under reduced pressure and the residue was acidified with 2N hydrochloric acid extracted with ethyl acetate (×100 mL). The combined ethyl acetate layers were washed with water (75 mL), brine (50 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using ethyl acetate to give the title compound (3.0 g, 66%) as a syrupy liquid.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH3:16])[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH3:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[C:8]1[S:7][N:6]=[C:5]([O:21][CH2:17][C:18]#[C:19][CH3:20])[N:9]=1
Reactant: CC#CCO
Reactant: CC1CCCCC1c1nc(S(C)(=O)=O)ns1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCCCC2C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.4 %

Procedure:
160 mg of 3-methylsulfonyl-5-(2-methylcyclohexyl)-1,2,4-thiadiazole and 52 mg of 2-butyn-1-ol were dissolved in 1.5 ml of N,N-dimethylformamide, 32 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours at room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 39 mg of 5-(2-methylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (10)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([CH:18]=[O:19])=[CH:6]2.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([CH2:18][OH:19])=[CH:6]2
Reactant: COCCNc1nc2ccc(OC)cc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCNc1nc2ccc(OC)cc2cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 6-methoxy-2-(2-methoxyethylamino)quinoline-3-carbaldehyde SLA 47060 (0.895 g, 3.4 mmol) in THF (34 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.13 g, 3.4 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (10 mL). After stirring for 15 min at that temperature, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give (6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methanol SLA 47064A as a yellow oil (0.90 g, 100% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:20])[CH2:18][OH:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH3:34][S:35]([O:19][CH2:18][C:17]([S:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:6]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:7][C:8]=2[CH:13]=1)(=[O:16])=[O:15])([CH3:20])[CH3:21])(=[O:37])=[O:36]
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CO)ccc2n1CC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)COS(C)(=O)=O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-1-ol (Step H, 356 mg, 0.94 mmol) in dichloromethane (8 mL) were added triethylamine (157 μL, 1.13 mmol) and methanesulfonyl chloride (87 μL, 1.13 mmol) at 0° C. The mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (30 mL×3). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude title compound (411 mg) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[C:19]#[N:20]>C(OCC)C>[Cl:17][C:18]([Cl:22])([Cl:21])[C:19](=[NH:20])[O:9][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: OC(c1ccc(Br)cc1)c1ccsc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N=C(OC(c1ccc(Br)cc1)c1ccsc1)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
To a solution of (4-bromophenyl)(thien-3-yl)methanol from step 1 (632 mg, 2.36 mmol) in diethyl ether (2.5 mL) at 0° C. was added sodium hydride (6 mg, 0.24 mmol). Then trichloroacetonitrile was added dropwise (237 μL, 2.36 mmol) over 15 minutes and the reaction was allowed to warm to room temperature for 3 hours. The reaction was then filtered over celite and concentrated under reduced pressure. The resulting crude compound was used as such in the next step.
Reaction SMILES: [CH:1]1([S:4]([NH2:7])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21](O)=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[CH2:15][C:14]2([CH3:37])[CH3:36].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([C:21]([NH:7][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])=[O:22])[CH:20]=1)[NH:17][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:25]=1)[CH2:15][C:14]2([CH3:37])[CH3:36]
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(=O)(=O)C3CC3)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.8 %

Procedure:
To a suspension of cyclopropanesulfonic acid amide (1.1 g, 9.1 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (361 mg, 9 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A63. A solution of 6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (520 mg, 1.3 mmol) and 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B63. Solution B63 was added to Solution A63 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (25 mg, 4%) as a white solid: MS (ESI) M+1=504.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][N:23]2[C:31](=[O:32])C3C(=CC=CC=3)C2=O)[C:19](C(OCC)=O)=[C:18]([NH:39][C:40]2[CH:41]=[C:42]([CH3:46])[CH:43]=[CH:44][CH:45]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[O:32]=[C:31]1[C:19]2[C:18]([NH:39][C:40]3[CH:41]=[C:42]([CH3:46])[CH:43]=[CH:44][CH:45]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[N:21][C:20]=2[CH2:22][NH:23]1
Reactant: CCOC(=O)c1c(CN2C(=O)c3ccccc3C2=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc3c2C(=O)NC3)c1
Temperature: 65 °C
Reaction time: 12 h
Yield: 44.2 %

Procedure:
A mixture of ethyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-((1,3-dioxoisoindolin-2-yl)methyl)-6-(m-tolylamino)pyrimidine-5-carboxylate (109 mg, 0.174 mmol) and hydrazine hydrate (36.5 mg, 0.729 mmol) in EtOH (2 mL) was stirred at 65° C. for 12 h. After cooling, the mixture was concentrated under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined organic layers were washed with aqueous NaHCO3, water, and brine, were filtered through SiO2, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from EtOAc/hexanes and filtered to give the title compound (34.8 mg). The filtrate was concentrated and triturated with IPE to give a second batch (20.3 mg) of the title compound (total 65.1 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24-1.79 (m, 17H), 2.32 (s, 3H), 3.84 (br s, 1H), 4.06 (br s, 1H), 4.14 (s, 2H), 6.55-6.70 (m, 1H), 6.87-7.04 (m, 2H), 7.20-7.24 (m, 1H), 7.40-7.48 (m, 1H), 7.68-7.80 (m, 1H), 8.01-8.06 (m, 1H), 8.56-8.59 (m, 1H). [M+H] calc'd for C24H33N6O3, 453. found, 453.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Cl:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:18]=[CH:17][C:10]([O:11][C:12]([CH3:15])([CH3:16])[CH2:13][O:14][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:9][CH:8]=1
Reactant: CC(C)(CO)Oc1ccc(Cl)cc1
Reactant: NS(=O)(=O)Cl
Product: CC(C)(COS(N)(=O)=O)Oc1ccc(Cl)cc1
Yield: 58 %

Procedure:
The title compound was prepared by procedures of Example 28 from sulfamoyl chloride and 2-(4-chlorophenoxy)-2-methylpropanol to give white solid, mp 76°-79° C., in 58% yield.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[OH-].[Na+]>O>[CH3:1][O:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Oc1cc2ccccc2cc1O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dimethylsulfate (32 ml) was added to the solution of 2,3-dihydroxynaphthalene (32 g) and sodium hydroxide (10 M, 32 ml) in water (300 ml). After being stirred for six hours at room temperature, the side product 2,3-dimethoxynaphthalene was filtered off (yield 16.6 g). The water phase was acidified, stirred on ice bath, filtered, washed with water and recrystallized from ethanol-water (3:2). Yield: 13.5 g, melting point 108-109° C.