Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1.N1C=CC=CC=1>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21]1)=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Nc1ccccc1C1Cc2ccccc2N1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)Nc1ccccc1C1Cc2ccccc2N1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Octyl chloroformate (2.00 ml) was added dropwise to a solution of 2.15 g 2-(2-aminophenyl)-2,3-dihydro-1H-indole and 2.00 ml pyridine in 35 ml CH2Cl2 at 0° C. The solution was stirred five hours at 0° C. and then quenched with water. The organic layer was separated, washed with 5% HCl and saturated NaCl solution, dried (MgSO4), and concentrated to yield a solid. Purification by flash chromatography using CH2Cl2 /hexane (1:2) as eluent gave 1.74 g solid, m.p. 99°-102° C.
Reaction SMILES: C(OC([N:11]1[CH:16]2[CH2:17][CH2:18][CH2:19][CH:12]1[C:13](=[O:31])[N:14]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:15]2=[O:20])=O)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[C:25]1([CH2:24][CH2:23][CH2:22][CH2:21][N:14]2[C:15](=[O:20])[CH:16]3[NH:11][CH:12]([CH2:19][CH2:18][CH2:17]3)[C:13]2=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1C2CCCC(C(=O)N1CCCCc1ccccc1)N2C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1C2CCCC(N2)C(=O)N1CCCCc1ccccc1
Yield: 92.4 %

Procedure:
2,4-Dioxo-3-(4-phenylbutyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound 13, 0.57 g, 1.36 mmol) was dissolved in THF (3 mL), and 10% palladium on activated carbon (0.12 g) was added. Hydrogen was applied via balloon for 1 hour. The black suspension was then filtered through compacted Celite, and the THF was removed by high-vacuum rotary evaporator to give Compound 14 (0.36 g, 92%) as a thick oil, which was of sufficiently good quality to be advanced to the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:34])[N:28]2[CH2:31][CH:32]=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:32][CH2:31][N:28]2[C:29]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:30]=3)[CH:25]=[CH:26][C:27]2=[O:34])[CH2:4][C@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@@H]1CNC[C@@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ccc(=O)n(CCN3C[C@@H](CNC(=O)OCc4ccccc4)[C@@H](O)C3)c2c1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3S,4R)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (300 mg, 1.20 mmol) and [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (260 mg, 1.12 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (762 mg, 3.6 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (337 mg, 62%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.C(N(C(C)C)CC)(C)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)=[N:2]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCCNc1nsc2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCNc1nsc2ccccc12)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-(Benzo [d]isothiazol-3-yl)ethane-1,2-diamine (50 mg, 0.26 mmol) was dissolved in anhydrous dichloromethane (5 mL) with diisopropylethylamine (50 μL, 0.28 mmol). The solution was cooled on an ice-water bath and then a solution of 4-chlorobenzoyl chloride (36 μL, 0.28 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2 h while warming to room temperature. The solution was washed with water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes, and selected fractions were combined and concentrated under reduced pressure to yield N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chlorobenzamide as a white solid, (50 mg). 1H NMR (300 MHz, DMSO-d6): 8.7 (broad s, 1H), 8.1 (d, 1H), 7.9 (m, 3H), 7.5 (m, 4H), 7.4 (m, 1H), 3.6 ppm (m, 4H). MW=332 confirmed by LC-MS, tr=3.89 min (Method B) MH+=333.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[C:11](OC(=O)C)(=[O:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4][OH:5]
Reactant: Cc1cccc(N)c1CO
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C)c1CO
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a suspension of 2-amino-6-methylbenzyl alcohol (30 g) in methylene chloride (300 ml) was added dropwise acetic anhydride (22.3 g) at 5° to 10° C. After being stirred for 3 hours, the mixture was neutralized with sodium bicarbonate aqueous solution to give precipitates. To said mixture was added chloroform to dissolve said precipitates and then the organic layer was washed with water and sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The resultant residue was suspended in diethyl ether and the precipitates were collected by filtration to give 2-methyl-6-acetamidobenzyl alcohol (25.30 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1.[H-].[Na+].Br[CH2:20][CH:21]=[CH2:22]>CN(C)C=O>[CH2:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][CH2:7][C:6]=2[CH:16]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCOC(=O)C1CCc2cc(O)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)CCC(C(=O)OCC)O2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a stirred mixture of 40 parts of ethyl 3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-carboxylate and 360 parts of N,N-dimethylformamide were added portionwise 8.6 parts of a sodium hydride dispersion 50% (foaming). After stirring for 30 minutes, a solution of 21.7 parts of 3-bromo-1-propene in 18 parts of N,N-dimethylformamide was added dropwise. Upon completion, the whole was heated to about 70° C. and stirring was continued for 22 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with 1,1'-oxybisethane. The extract was washed with a sodium chloride solution 10%, dried, filtered and evaporated. The oily residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 33.6 parts (70.2%) of ethyl 3,4-dihydro-6-(2-propenyloxy)-2H-1-benzopyran-2-carboxylate as a residue (intermediate 28).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([O:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C.Cl>O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:10]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:9]
Reactant: Nc1nccs1
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)C(F)(F)F
Reaction time: 1.25 h
Yield: 23.1 %

Procedure:
Into a 250 ml three-necked flask equipped with magnetic stirrer, thermometer, dropping funnel and nitrogen inlet, 5.0 g (49.9 mmol) of 2-aminothiazol and 14.3 g (99.85 mmol) of ethyltrifluoroacetate in 100 ml of tetrahydrofuran are introduced. A solution of 14.4 g (124.8 mmol) of potassium-t-butylate in 50 ml of tetrahydrofuran is added dropwise within 15 minutes to the stirred brown solution, whose internal temperature is kept in the range 20-25° C. using an ice bath. Stirring is continued for another 75 minutes, then 300 ml of a buffer solution is added and pH 7 is adjusted by addition of 2N aq. HCl. Extraction with 300 ml of ethyl acetate is carried through 3 times, the combined organic phases are washed with 250 250 ml of water, dried over MgSO4, and filtered. After evaporating the solvent, the crude product is recrystallized from 2-propanol, yielding 2.26 g of the title product.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].Cl.[CH3:21][C:22]1[C:23]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:24][CH:25]=[C:26]([CH3:28])[N:27]=1>>[CH3:21][C:22]1[C:23]([N:29]2[CH2:30][CH2:31][N:32]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:19])([CH3:8])[CH3:9])=[CH:18][CH:17]=3)=[O:16])[CH2:33][CH2:34]2)=[N:24][CH:25]=[C:26]([CH3:28])[N:27]=1
Reactant: CC(C)(c1ccc(C(=O)O)cc1)N1CCCS1(=O)=O
Reactant: Cc1cnc(N2CCNCC2)c(C)n1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(C(C)(C)N4CCCS4(=O)=O)cc3)CC2)c(C)n1
Yield: 53.9 %

Procedure:
Using 4-[1-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1-methylethyl]benzoic acid (100 mg) described in Preparation Example 39 and (3,5-dimethylpyrazin-2-yl)piperazine hydrochloride (81 mg) described in Preparation Example 104 and by the reaction and treatment in the same manner as in Example 86, the title compound (87 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]3=[O:20])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>C1COCC1>[I:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH:10]3[CH2:11][CH2:12][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:8][CH2:9]3)[C:15](=[O:20])[CH2:16]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: O=C1CNCCN1CC1CCN(c2ccncc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc(I)cc2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 14.3 %

Procedure:
To a mixture of 1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (549 mg), sodium bicarbonate solution (5 ml), ethyl acetate (10 ml) and THF (5 ml) was added dropwise, under ice-cooling, a solution of 4-iodobenzenesulfonyl chloride (1.21 g) in THF (10 ml), and the mixture was stirred at 0° C. for 1 hour. The separated organic layer was washed with saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9: 1→1:1) and washed with water to give colorless crystals of 4-(4-iodobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (155 mg). A part of the crystals were treated with hydrochloric acid to give colorless crystals of the title compound as hydrochloride.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>O>[F:3][C:4]1[CH:12]=[C:11]([O:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccc(O)cc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
In a 100 ml-reaction vessel, 12.1 g (1.83×10-1M) of potassium hydroxide and 50 ml of water were placed, followed by cooling to 0° C. To the mixture, 12.0 g (7.69×10-2M) of 2-fluoro-4-hydroxybenzoic acid was added and dissolved therein. To the solution, 7.9 g (7.74×10-2M) of acetic anhydride was added dropwise in 30 minutes at 0° C., followed by stirring for 2 hours. After stirring, the reaction mixture was acidified with 6N-hydrochloric acid to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water and drying to obtain 9.5 g of 2-fluoro-4-acetoxybenzoic acid (Yield: 62.4%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=2[CH:7]=1.Cl.[NH2:15][OH:16].C(N(CC)C(C)C)(C)C>C(O)C>[OH:16][NH:15][C:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([CH2:2][OH:1])=[CH:7][C:6]=2[CH:8]=1)=[NH:13]
Reactant: N#Cc1ccc2oc(CO)cc2c1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)c1ccc2oc(CO)cc2c1
Temperature: 71 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A mixture of the product of Step B (0.22 g; 1.27 mmol) and HCl×NH2OH (0.18 g; 2.59 mmol) and N,N-diisopropylethylamine (DIPEA) (0.67 ml; 3.82 mmol) in ethanol (EtOH) (2 ml) was stirred for 3 h at ˜71° C. The solvents were removed in vacuo and the residue was treated with H2O (3 ml) and the product was taken up by EtOAc (3×15 ml). The combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title compound (0.2 g; 76%), as colourless solid, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[C:18]([NH2:20])[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:20][C:18]1[N:19]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[S:16][C:17]=1[C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(N)c(C(=O)c3cccc(F)c3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(NC2CCNCC2)sc1C(=O)c1cccc(F)c1
Reaction time: 1 h
Yield: 72 %

Procedure:
4-[4-Amino-5-(3-fluorobenzoyl)thiazol-2-ylamino]piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 1.95 mmol) (Example 3) was dissolved in a mixture of trifluoroacetic acid (16 mL) and methylene chloride (30 mL). After 1 hr, all solvent was removed and the residue dissolved in methylene chloride (300 mL). This was washed with 10% Na2CO3 (50 mL), dried (Na2SO4) and concentrated to give a semi solid. This was triturated with ethyl ether and filtered to give 450 mg (72% yield) of [4-amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluorophenyl)methanone. 1H NMR (DMSO−d6, 300 MHz) δ1.38 (m, 2H, CH2), 1.88 (m, 2H, CH2), 2.95 (m, 2H, CH2), 3.32 (brd, 2H, CH2), 3.6-4.0 (broad, 1H, CH), 3.78 (s, 3H, OCH3), 7.31 (t, 1H, Aromatic), 7.38 (d, 1H, Aromatic), 7.48 (t, 1H, Aromatic), 7.51 (q, 1H, Aromatic), 8.01 (brd, 1H, NH), 8.48 (brd, 1H, NH), 8.70 (brd, 1H, NH). LR-MS-ES(±): Compatible with 320 MW.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([N:18]1[CH2:23][CH2:22]O[CH2:20][CH2:19]1)=[O:17])=[CH:5]2.Cl.[F:25][C:26]1([F:32])CCNCC1>>[F:25][C:26]1([F:32])[CH2:20][CH2:19][N:18]([C:16]([C:6]2[N:7]([CH2:11][C:12]([F:15])([F:13])[F:14])[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:17])[CH2:23][CH2:22]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Agent: Cl
Product: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCC(F)(F)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 5-hydroxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid (Intermediate 1, step 3) and 4,4-difluoropiperidine hydrochloride. The title product was obtained in 80% as white solid. MS (m/e): 361 (M−H−, 100%).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1[C:22]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([C:22]2[C:21]([F:20])=[CH:26][CH:25]=[CH:24][N:23]=2)([OH:31])[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1ncccc1F
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ncccc1F
Yield: 18 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(3-fluoropyridin-2-yl)but-3-yn-2-ol to give the titled compound as an off-white solid (27 mg, 18%).
Reaction SMILES: [C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16](O)=[O:17])[C:10]2=[O:34])[CH:4]=1)#[N:2].C([N:37](CC)CC)C.ClC(OCC)=O.[NH4+].[OH-]>C1COCC1.CCOC(C)=O>[C:1]([C:3]1[S:7][CH:6]=[C:5]([CH2:8][N:9]2[CH2:13][CH2:12][C@H:11]([N:14]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][C:16]([NH2:37])=[O:17])[C:10]2=[O:34])[CH:4]=1)#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(S(=O)(=O)N(CC(N)=O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid (0.40 g, 0.80 mmol) in 6 mL of THF at -15° C. is added triethyl amine (0.10 g, 0.96 mmol) and ethyl chloroformate (0.09 g, 0.84 mmol). The solution is stirred for 1 hour. After this time, NH4OH (0.07 mL, 0.90 mmol) is added and the solution is allowed to warm to ambient temperatures. After 16 hours, the solution is diluted with EtOAc. The solution is washed with 1 N HCl, sat. NaHCO3 and sat. NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The title compound (0.28 g, 0.56 mmol) is obtained as a white foam.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([N:18]=[C:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1N=C(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2cnc3ccccc3c2n1NC(CC)CC
Reaction time: 24 h
Yield: 56.4 %

Procedure:
A solution of N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropylidene)amine (1.78 g, 5.73 mmol) in 20 mL of methanol was treated with NaBH4 (0.867 g, 22.9 mmol) and CeCl3.7H2O (15 mg, catalytic) and stirred under an atmosphere of nitrogen. After 24 h, the reaction was concentrated under reduced pressure, dissolved CHCl3, washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a yellow/green syrup. Chromatography (SiO2, 93:7 CHCl3:MeOH) gave N-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)(1-ethylpropyl)amine (1.01 g) as a yellow/green oil.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.O=[C:24]1[NH:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1>O1CCCC1>[S:10]=[C:24]1[NH:29][CH2:28][CH2:27][N:26]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCNC(=S)C1

Procedure:
Lawesson's reagent (10.1 g, 20 mmol) was added to a solution of benzyl 3-oxo-1-piperazinecarboxylate (10 g, 43 mmol) in tetrahydrofuran (110 mL), and the reaction heated under reflux for 4 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between 1N sodium hydroxide solution (150 mL) and ethyl acetate (250 mL), and the layers separated. The organic extract was washed with 1N sodium hydroxide solution (2×100 mL), then brine (100 mL), and the combined aqueous solutions extracted with ethyl acetate (200 mL). The combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (98:2) as eluant to afford the title compound as a tan-coloured solid, 6.7 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19](=[CH2:24])[C:20]([F:23])([F:22])[F:21])=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1.[H][H]>C1COCC1.CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([CH:19]([CH3:24])[C:20]([F:22])([F:21])[F:23])=[N:14][N:13]=[CH:12]3)=[CH:4][CH:3]=1
Reactant: C=C(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(c1nncc2cc(Nc3ccc(F)cc3)ccc12)C(F)(F)F
Reaction time: 3 h

Procedure:
A solution of N-(4-fluorophenyl)-1-(1,1,1-trifluoroprop-2-en-2-yl)phthalazin-6-amine (0.067 g, 0.20 mmol) in 4 mL of THF/EtOH (3/1) was treated with palladium (10% wt. on activated carbon, 0.021 g, 0.020 mmol); and stirred at RT with a balloon of hydrogen. After 3 h, the reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give the crude product. The material was purified on an ISCO column (12 g, 50-75% EtOAc in hexanes) to afford the title compound as a light yellow solid. MS (ESI, pos. ion) m/z: M+1=366.0.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[O:4]1[CH2:5][CH2:6][CH:2]([O:1][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCOC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
To a solution of 3-hydroxy tetrahydrofuran (2.5 g, 28.0 mmol) in anhydrous pyridine (60 mL) at room temperature was added 4-toluene sulfonyl chloride (6.49 g, 34.0 mmol). After stirring the reaction mixture for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30% ethyl acetate in heptane to afford 3.5 g (51% yield) of the desired product as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][S:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:33])[CH3:32])[CH2:28]3)=[CH:23][CH:22]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:35](F)(F)[C:36](O)=O>C(Cl)(Cl)Cl>[CH2:17]([O:16][C:14]([C:11]1([CH2:19][S:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][N:27]([C:31](=[O:33])[CH3:32])[CH2:28]3)=[CH:23][CH:22]=2)[CH2:10][CH2:9][N:8]([C:36]2[CH:35]=[CH:13][N:8]=[CH:9][CH:10]=2)[CH2:13][CH2:12]1)=[O:15])[CH3:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C1(CSc2ccc3c(c2)CN(C(C)=O)CC3)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(CSc2ccc3c(c2)CN(C(C)=O)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-ylthiomethyl)-4-ethoxycarbonylpiperidine-1-carboxylic acid tert-butyl ester (221 mg) in chloroform (0.5 ml) was added trifluoroacetic acid (1 ml), and the mixture was stirred at room temperature for 10 min. After completion of the reaction, the solvent was evaporated and to the obtained residue were added ethanol (3 ml), triethylamine (0.39 ml) and 4-chloropyridine hydrochloride (70 mg). The mixture was stirred in a sealed tube at 150° C. for 2 days. After completion of the reaction, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (5% methanol-chloroform) and dried under reduced pressure to give the title compound (63 mg).