Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6][CH2:5]1.C(O[CH:21]=[N:22][C:23]1[S:24][C:25]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])=[C:26]([CH3:33])[C:27]=1[C:28](OCC)=[O:29])C>C(O)C>[CH3:33][C:26]1[C:27]2[C:28](=[O:29])[N:1]([CH2:2][CH2:3][N:4]3[CH2:5][CH2:6][N:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[O:16][CH3:17])[CH2:8][CH2:9]3)[CH:21]=[N:22][C:23]=2[S:24][C:25]=1[C:34](=[O:38])[N:35]([CH3:37])[CH3:36]
Reactant: CCOC=Nc1sc(C(=O)N(C)C)c(C)c1C(=O)OCC
Reactant: COc1ccccc1N1CCN(CCN)CC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CCn2cnc3sc(C(=O)N(C)C)c(C)c3c2=O)CC1
Reaction time: 8 h

Procedure:
1.9 g (8.0 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine were added to 2.4 g (7.8 mmol) of 2-ethoxymethyleneamino-3-carboethoxy-4-methyl-5-dimethylcarbamoylthiophene in 30 ml of ethanol, and the mixture was boiled at reflux for 2 h. After standing overnight, the product crystallized out and was filtered off with suction and washed with a little ethanol. 2.2 g (62%) of product, having a m.p. of 188-190° C., were isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.O[CH:10]1[CH2:14][CH2:13][O:12][CH2:11]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: Oc1ccc(Br)nc1
Reactant: OC1CCOC1
Product: Brc1ccc(OC2CCOC2)cn1

Procedure:
The title compound was prepared from 2-bromo-5-hydroxypyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): MS (EI): 243 and 245 M+.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[C:12]([SiH2:16][O:17][C:18]([CH3:33])([CH3:32])[C:19]1[CH:20]=[C:21]([NH2:31])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:31][C:21]2[CH:22]=[CH:23][C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[C:19]([C:18]([CH3:33])([CH3:32])[O:17][SiH2:16][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:20]=2)=[N:4][CH:3]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)ccc1N1CCOCC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(Nc2ncc(Br)n3ccnc23)ccc1N1CCOCC1
Yield: 21.5 %

Procedure:
In the same way as described in the general procedure for amine displacement using 5,8-dibromo-imidazo[1,2-a]pyrazine (0.534 g, 1.94 mmol), 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-morpholin-4-yl-phenylamine (0.751 g, 2.33 mmol), N,N-diisopropyethylamine (0.31 mL, 1.8 mmol) and iso-propanol (10 mL). Purification by silica gel column chromatography eluting with 7:3 petroleum ether:ethyl acetate followed by trituration with diethyl ether affords the title compound (0.216 g, 17%).
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[C:7](#[N:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:1][C:2]([CH3:6])=[C:3]([CH3:4])[C:8]=1[C:7]#[N:11]
Reactant: CC(=O)C(C)S
Reactant: N#CCC#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1sc(N)c(C#N)c1C
Temperature: -2 °C
Yield: 64.2 %

Procedure:
A solution of 3-mercapto-2-butanone (1.00 kg, 9.0 mole, 93.6% assay) in 2.0 L SDA 3C 200 Proof, absolute Ethanol (Ethanol) is prepared in a 5 L 1N RBF fitted with torian and transfer tubing. Malononitrile (588.8 g, 8.9 mole) is dissolved in 5.0 L Ethanol and cooled to 4° C. at which point triethylamine (250 mL, 1.8 mole, 0.2 eq) is added with a 560 mL ethanol rinse. The anionic malononitrile solution is cooled to −2° C. and the 3-mercaptobutanone solution is added over 1.3 hrs at −1 to −5° C. After an hour, the reaction shows less than 0.1% malononitrile. The reaction is concentrated on the rotovap (40° C. bath) to a slurry of approximately 2.5 L and 3.0 L of heptanes are added. The slurry is cooled to 5° C. for 30 minutes and the solids collected by filtration. The solids are rinsed with 2.5 L of 20% Ethanol in heptanes in 7 portions. The excess solvent is removed on the filter, and the wet cake dried in a vacuum oven overnight at 40° C. and full vacuum to give an off white solid as 2-amino-4,5-dimethylthiophene-3-carbonitrile (870 g, 64.1% yield, 99.7% purity shown by HPLC). The filtrates are reconcentrated to an oily slurry which is filtered and rinsed with 0.5 L of 20% Ethanol in heptanes. The second crop of solids is dried separately (47 g, 3.5% yield, 98.6% purity shown by HPLC). NMR (400 MHz, DMSO-d6) δ 1.93 (d, J=1.2 Hz, 3H), 2.07 (d, J=1.2 Hz, 3H), 3.33 (s, 2H). MS 153 (MH+). HPLC Retention Time: approximately 10.9 minute (Phenomenex Luna C18 (2) column, acetonitrile/water with 0.1% AcOH).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:30](=[O:43])[NH:31][C:32]3[S:33][C:34]4[C:39]([N:40]=3)=[CH:38][CH:37]=[C:36]([O:41][CH3:42])[N:35]=4)[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])C.Cl>O.CO>[CH:25]1([CH2:24][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([N:11]3[CH2:12][CH2:13][CH:8]([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)[C:30](=[O:43])[NH:31][C:32]2[S:33][C:34]3[C:39]([N:40]=2)=[CH:38][CH:37]=[C:36]([O:41][CH3:42])[N:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(OC)nc4s3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(=O)(=O)N4CCC(C(=O)O)CC4)cc3)sc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
Sodium hydroxide (12 mg, 0.2996 mmol) was dissolved in a minimum amount of water and added to a solution of title compound F, 1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-4-carboxylic acid ethyl ester (90 mg, 0.1498 mmol) in methanol. The reaction was stirred at room temperature overnight, poured into 1N hydrochloric acid, and extracted with ethyl acetate. Extracts were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow foam (63 mg, 73%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.05-1.16 (m, 2 H) 1.36-1.47 (m, 2 H) 1.49-1.61 (m, 5 H) 1.66-1.72 (m, 3 H) 1.75 (s, 1 H) 1.78-1.80 (m, 1 H) 1.92-2.02 (m, 1 H) 2.08-2.18 (m, 1 H) 2.40 (t, J=9.85 Hz, 2 H) 3.35 (d, J=11.37 Hz, 2 H) 3.82-3.92 (m, 4 H) 6.74 (d, J=8.59 Hz, 1 H) 7.59-7.67 (m, 4 H) 7.79 (d, J=8.84 Hz, 1 H) LC/MS 573.1 (M+1) 571.4 (M−1) EC50 in primary enzyme assay 7.1 μM
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[C:28]([N:31]1[CH2:35][CH2:34][NH:33][C:32]1=[O:36])(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:35][CH2:34][N:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=2)[C:32]1=[O:36])(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)c(S(C)(=O)=O)c2)C1=O
Yield: 79.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.36 g) described in Preparation Example 112 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (1.20 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH2:21]([NH2:23])[CH3:22]>CN(C)C=O.O>[Cl:8][C:7]1[C:2]([NH:23][CH2:21][CH3:22])=[N:3][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=1
Reactant: Clc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reactant: CCN
Solvent: O
Solvent: CN(C)C=O
Product: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Reaction time: 6 h

Procedure:
2,3-Dichloro-5,6-diphenylpyrazine (2.00 g, 0.0066 moles), is suspended in dimethylformamide (DMF) (12 ml) and treated with a solution of ethylamine (70% in water) (3.5 ml) in DMF (6ml) and the mixture is warmed at 40°-45°C for 30 minutes then allowed to stand at room temperature for 6 hours. The solution is diluted with water (80 ml) and after standing overnight the solid is filtered off, washed with water and dissolved in hot ethyl alcohol, filtered, concentrated and cooled to yield 1.19 g of greenish-yellow solid. m.p. 115°-122°. This material is recrystallized from an ethyl alcohol-hexane mixture, yield 0.84 g, m.p. 121°-125°. Identity of the product is confirmed by infrared, nuclear magnetic resonance and mass spectra.
Reaction SMILES: C([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[C:17]1([CH:12]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:24][CH2:23]3)[C:15](=[O:16])[NH:14][CH2:13]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1NCC(c2ccccc2)C12CCN(Cc1ccccc1)CC2
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C1NCC(c2ccccc2)C12CCNCC2
Yield: 63.2 %

Procedure:
A suspension of rac-8-benzyl-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one (28.8 g, 90 mmol) in MeOH: DCM (4: 1, 500 ml) was hydrogenated in the presence of Pd (10% on C, 14 g, 132 mmol) at 2 bar for 48 h at room temperature. After filtration over celite, the reaction mixture was evaporated and the residue dissolved in NaOH (2 N, 200 mnL). The product was extracted with DCM (3×150 mL) and the combined organic extracts dried over sodium sulfate. Filtration and evaporation afforded the title compound (13.1 g, 63%) as a white solid after trituration from diethylether. MS: m/e=231.4 (M+H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][OH:23])[C:16]=2[N:17]=1>>[CH3:12][C:13]1[S:14][C:15]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][O:23][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[C:16]=2[N:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1nc2c(s1)CCCC2CO
Product: Cc1ccc(S(=O)(=O)OCC2CCCc3sc(C)nc32)cc1
Yield: 89 %

Procedure:
This compound is prepared by action of p-toluenesulfonyl chloride on above alcohol (IV), according to the process of Example 1. M.p.=97°-98° C. Yield: 89%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][Si](Cl)(C)C>CO>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([O:9][CH3:12])=[O:8]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(O)c(C(=O)O)c1
Solvent: CO
Product: COC(=O)c1cc(C)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylsalicylic acid (7.24 g) in methanol (250 ml) was added trimethylsilyl chloride (60 ml). The mixture was heated at reflux for 2 hours and stirred at room temperature overnight. A further 60 ml trimethylsilyl chloride was added and the mixture heated at reflux for 6 hours. The mixture was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated to give the crude product. Yield 5.87 g. Used directly in the next step.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>O>[C:16]([N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]1[C:2]([Cl:1])([Cl:14])[Cl:15])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Solvent: O
Product: CC(=O)N1C(=O)c2ccccc2OC1C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4-Dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--4.0 g.) was stirred with acetic anhydride (40 ml.) on a steam-bath for 10 hours. The reaction mixture was cooled to room temperature, poured into water (400 ml.) and stirred for 3 hours, and the oil which separated was extracted into diethyl ether. The extract was dried and the solvent was evaporated to leave an oil, which was purified by column chromatography on "Kieselgel 60" (trade mark) silica, and the column was eluted with 10% v/v ethyl acetate in toluene. 25 Ml. fractions were collected, fractions 1-7 were combined, and the solvent was evaporated to give 3-acetyl-3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one as an oil. The n.m.r. spectrum in hexadeuterio-dimethylsulphoxide showed the following characteristic peaks (δ values):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([OH:26])[CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1.O.NN>C(O)C>[NH2:15][CH2:14][C@@H:13]([OH:26])[CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:27]=[CH:28][C:29]([Cl:30])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
(S)-2-[3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl]-1H-isoindole-1,3(2H)-dione (4 g) in ethanol (100 ml) was treated with 20 ml of hydrazine monohydrate and the resulting mixture was refluxed for 3 h. The reaction was cooled and filtered. The filtrate was evaporated and the product was chromatographed (ethyl acetate) to give the title compound as a yellow oil which solidified on standing (2.5 g).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([F:48])=[CH:21][C:22]=1[C:23]1[C:28]2[S:29][C:30]([C:32]3[C:37]([F:38])=[CH:36][N:35]=[C:34]([NH:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][NH:44][C:43]4=[O:47])[N:33]=3)=[CH:31][C:27]=2[CH:26]=[CH:25][CH:24]=1)C)(C)(C)C>ClCCl>[F:38][C:37]1[C:32]([C:30]2[S:29][C:28]3[C:23]([C:22]4[C:17]([CH2:16][NH:14][CH3:13])=[CH:18][N:19]=[C:20]([F:48])[CH:21]=4)=[CH:24][CH:25]=[CH:26][C:27]=3[CH:31]=2)=[N:33][C:34]([NH:39][CH2:40][CH2:41][N:42]2[CH:46]=[CH:45][NH:44][C:43]2=[O:47])=[N:35][CH:36]=1
Reactant: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4cc[nH]c4=O)ncc3F)sc12
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Add trifluoro-acetic acid (1 mL) to a solution of [6-fluoro-4-(2-{5-fluoro-2-[2-(2-oxo-2,3-dihydro-imidazol-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophen-7-yl)-pyridin-3-ylmethyl]-methyl-carbamic acid tert-butyl ester (280 mg, 0.47 mmol) in dichloromethane (1 mL). Stir for 1 hour and remove solvent on a rotovap. Wash with saturated NaHCO3 and extract in dichloromethane, wash with saturated aqueous sodium chloride, dry over Na2SO4, and filter. Remove solvent on a rotovap to obtain the solid and dry under vacuum to afford the product (196 mg). MS (ES) m/z 494 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([OH:12])[C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Cn1cnc2cc(Br)cc(O)c21
Reactant: C[C@H](OS(C)(=O)=O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C[C@H]([C@@H](C)Oc2cc(Br)cc3ncn(C)c23)CC1=O
Temperature: 90 °C

Procedure:
To a solution of 5-bromo-1-methyl-1H-benzo[d]imidazol-7-ol 2.56 (15 mg, 0.066 mmol) in DMF (2 mL) was added (S)-1-((R)-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-3-yl)ethyl methanesulfonate 1.17 (41 mg, 0.312 mmol) and Cs2CO3 (33 mg, 0.1 mmol) and the reaction mixture was heated at 90° C. for 1 h. The reaction mixture was then diluted with ethyl acetate, washed with water (3×), brine and dried over anhydrous magnesium sulfate. Filtration, followed by concentration gave (R)-4-((R)-1-(5-bromo-1-methyl-1H-benzo[d]imidazol-7-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 2.57, which was used for next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:9][N:8]2[C:29]([O:31][CH3:32])=[O:30])=[CH:17][CH:18]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 110.2 %

Procedure:
To a solution of methyl 2-(4-chlorobenzyl)piperidine-4-carboxylate (3.72 g, 13.2 mmol) and DIPEA (4.85 mL, 27.78 mmol) in DCM (100 mL) was added methyl chloroformate (1.431 mL, 18.48 mmol) in DCM (50 mL) over 30 minutes. The reaction solution was stirred overnight (16 h). The organic phase was washed with satd NaHCO3, dried using a phase separator and evaporated to yield dimethyl 2-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (4.74 g, 110%) as a yellow oil. MS m/z 326, 328 (M+H)+
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:18]=2[N:19]=1.CN.[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3cc(OC(F)(F)F)ccc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(OC(F)(F)F)ccc3s1)n2C
Yield: 63.9 %

Procedure:
1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid methylamide (27 mg) was prepared by following General Procedure F using 1-methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylic acid (41 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 423.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CS(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[CH2:7][CH:8]([CH:10]=[O:11])[CH2:9]1
Reactant: OCC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1CN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of {1-[2,4-bis(trifluoromethyl)benzyl]azetidin-3-yl}methanol (313 mg) and triethylamine (607 mg) in DMSO (5 mL) was added sulfur trioxide pyridine complex (477 mg) at room temperature. The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (202 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([N+:18]([O-])=O)=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1.[Cl-].[Ca+2].[Cl-].C>C(O)C.O.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([NH2:18])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1
Reactant: COC(=O)C(C)c1ccc2c(c1)Cc1cc([N+](=O)[O-])ccc1-2
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: COC(=O)C(C)c1ccc2c(c1)Cc1cc(N)ccc1-2
Yield: 85.7 %

Procedure:
A slurry of 7-nitro-α-methylfluorene-2-acetic acid methyl ester (13.1 g) in 78% ethanol (400 ml) is treated with a solution of calcium chloride (4.5 g) in water (6.1 ml), zinc dust (127 g) and charcoal (4.6 g) and the mixture refluxed for 2.5 hours. The hot mixture is filtered and the cake washed with hot 78% ethanol. The filtrate is diluted with water (800 ml) and extracted with chloroform. The chloroform extracts are dried (MgSO4) and evaporated to give 10.1 g of 7-amino-α-methylfluorene-2-acetic acid methyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cn1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCCCCl)cn1
Temperature: 25 °C
Yield: 134.5 %

Procedure:
Under a nitrogen atmosphere, a solution of 5-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.825 g of an 80% dispersion in mineral oil, 27.5 mmol) in DMF (15 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. Next, 1-chloro-3-iodopropane (4.49 g, 22.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 4 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 4.57 g of an oil.
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13]N)=[CH:9][CH:8]=2)[CH:6]=1.[Si]([O:22][CH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH:32]=O)[CH2:25][CH2:24]1)(C(C)(C)C)(C)C>C(O)C.O.C(O)C>[N:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]3[C:10](=[CH:9][CH:8]=2)[NH:13][CH:32]=[C:31]3[CH2:30][CH2:29][CH:26]2[CH2:25][CH2:24][CH:23]([OH:22])[CH2:28][CH2:27]2)[CH:6]=1
Reactant: NNc1ccc(-n2cnnc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(CCCC=O)CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: OC1CCC(CCc2c[nH]c3ccc(-n4cnnc4)cc23)CC1
Temperature: 140 °C

Procedure:
A stirred mixture of 4-(1,2,4-triazol-4-yl)phenylhydrazine hydrochloride (930 mg, 3.5 mmol) in ethanol/water (25 ml, 4:1), under nitrogen, was slowly treated with a solution of 4-[4-(tert-butyldimethylsilanyloxy)cyclohexyl]butyraldehyde (1 g, 3.5 mmol) in ethanol (5 ml). The reaction mixture was heated at 140° C. for 18 hours in a sealed tube, cooled and evaporated. The residue was purified by column chromatography on silica using methanol/dichloromethane as eluent to afford the title compound as a mixture of cis and trans isomers (1 g, 92%). MS, ES+, m/z=311 for (M+H)+, δ(250 MHz, d6-DMSO) 1.07-1.88 (11H, m), 2.71 (2H, t, J=7 Hz), 3.70-3.78 (1H, m), 4.26 (1H, d, J=3 Hz), 7.21-7.32 (2H, m), 7.47 (1H, d, J=9Hz), 7.76 (1H, d, J=2Hz), 9.02 (2H, s), 11.10 (1H, br s).