Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24]O)=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].O1CCCC1.CS(Cl)(=O)=O.O.[NH3:41]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:26]([F:29])([F:28])[F:27])[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([CH2:24][NH2:41])=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: OCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: N
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NCc1sc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
{2-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoro-methyl)-1,3-thiazol-5-yl}methanol (1.05 g) was added to tetrahydrofuran (30 mL). Then, tetrahydrofuran solution (10 mL) comprising methanesulfonyl chloride (0.3 g) was added dropwise thereto under ice cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for one hour. The resulting solution was added dropwise to a mixture solution, which was separately prepared to contain 28% ammonia water (50 mL), tetrahydrofuran (100 mL), and methanol (100 mL), under ice cooling. After stirring the mixture at room temperature for 12 hours, the reaction solution was poured over ice water, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was then purified by a silica gel chromatography to obtain the title compound (0.4 g, 45%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][C:20]([O:29][CH3:30])=[CH:21][C:22]=4[O:27][CH3:28])[N:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH:5]1[CH3:31])(=O)C.[OH-].[Na+]>Cl>[CH3:28][O:27][C:22]1[CH:21]=[C:20]([O:29][CH3:30])[CH:19]=[C:18]2[C:23]=1[C:24](=[O:26])[NH:25][C:16]([C:13]1[CH:14]=[CH:15][C:10]([N:7]3[CH2:8][CH2:9][NH:4][CH:5]([CH3:31])[CH2:6]3)=[CH:11][CH:12]=1)=[N:17]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)C(C)C4)cc3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNC(C)C4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.9 %

Procedure:
A solution of 2-(4-(4-acetyl-3-methylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.340 g, 0.80 mmol) in 2 N HCl (5 mL) was heated to reflux and stirred for 3 days. Then, the resulting solution was cooled to room temperature, basified with 2 N NaOH, extracted with CH2Cl2, and concentrated in vacuo. The material was purified by flash chromatography on silica gel, eluting with 50% to 100% of 92:7:1 CHCl3/MeOH/concentrate NH4OH in CH2Cl2, to afford the title compound (0.03 g, 9%). 1H NMR (300 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.08 (d, J=8.9 Hz, 2H), 6.99 (d, J=9.1 Hz, 2H), 6.67 (s, 1H), 6.46 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.62-3.79 (m, 2H), 2.90-3.04 (m, 1H), 2.57-2.85 (m, 4H), 2.20-2.39 (m, 1H), 1.03 (d, J=6.3 Hz, 3H). ESI MS m/z 381 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([CH2:26][NH:27][CH2:28][CH:29]=[CH2:30])[CH2:10]1.[CH3:31][S:32]([NH:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)(=[O:34])=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([CH2:26][N:27]([CH2:28][CH:29]=[CH2:30])[S:42]([C:39]2[CH:38]=[CH:37][C:36]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:41][CH:40]=2)(=[O:44])=[O:43])[CH2:10]1
Reactant: C=CCNCC1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: C=CCN(CC1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1)S(=O)(=O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
In a manner similar to Preparation 3, react 4-(2,6-dichlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-N-(2-propenyl)-2-piperazinemethanamine with 4-[(methylsulfonyl)amino]benzenesulfonyl chloride to obtain the title compound.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[C:11]([NH2:13])=[O:12].S(=O)(=O)(O)O>O1CCOCC1>[CH3:10][C:8]1[S:9][C:5]2[CH:4]=[CH:3][NH:13][C:11](=[O:12])[C:6]=2[N:7]=1
Reactant: COC(Cc1sc(C)nc1C(N)=O)OC
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: Cc1nc2c(=O)[nH]ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,2-Dimethoxy-ethyl)-2-methyl-thiazole-4-carboxylic acid amide (1.0 g, 4.3 mmol) was dissolved in 35 ml dioxane and 0.3 ml conc. sulfuric acid was added. The reaction mixture was stirred for 2 hrs at room temperature. The white suspension was cooled to 0° C. and stirred for 10 min. The suspension was filtered and washed with cold dioxane. The solid was dried for 1 hour at 50° C. and <30 mbar. The desired product was obtained as a white solid (0.7 g, 97%), MS: m/e=167.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].N12CCN(CC1)CC2>C(OC)(C)(C)C>[C:14](=[O:15])([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: O=C(Cl)Oc1ccccc1
Agent: C1CN2CCN1CC2
Solvent: COC(C)(C)C
Product: CN1C(C)(C)CC(OC(=O)Oc2ccccc2)CC1(C)C
Reaction time: 2 h

Procedure:
Into a 500 ml 3-neck flask was added 17.1 grams (0.1 mole) 1,2,2,6,6-pentamethyl-4-piperidinol and 300 mls of methyl t-butyl ether (MtBE). The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and dropping funnel containing 15.6 grams (0.1 mole) phenyl chloroformate. The phenyl chloroformate was slowly added to the 1,2,2,6,6-pentamethyl-4-piperidinol solution without any appreciable exotherm. Then 11.2 grams (0.1 mole) of 1,4-diazabicyclo(2.2.2)octane (DABCO) was added at room temperature. The temperature rose to 50° C. and a precipitate formed. The reaction was stirred for 2 hours, an additional 2 grams of DABCO and 1.25 grams of phenyl chloroformate was added, the reaction heated to reflux and refluxed 2 hours. The reaction mixture was cooled, transferred to a separatory funnel and washed with water to remove DABCO, DABCO hydrochloride and a small amount of 1,2,2,6,6-pentamethyl-4-piperidinol. The product was then extracted out of the MtBE layer with 100 mls of 5% HC1 diluted with water to 400 mls. The MtBE layer which contained diphenyl carbonate was discarded. The acid layer was made basic with 100 ml of 10% NaOH. The product was extracted out of the aqueous layer with 200 ml MtBE. The MtBE extract was washed with 100 ml 5% NaHCO3, dried over anhydrous MgSO4, filtered and the MtBE stripped off on a rotating evaporator under reduced pressure. The residue was a white solid weighing 20.4 grams (70.1% crude yield) which had a melting point of 63°-67° C. Liquid chromatography indicated the product was essentially one component. The infrared spectrum contained a strong carbonyl peak at 1755 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][CH:12]=[CH:13][N+:14]([O-:16])=[O:15])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:7]2[OH:8]
Reactant: O=C(O)c1cc(Cl)ccc1NC=C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1O

Procedure:
5-Chloro-2-(2-nitrovinylamino)benzoic acid (Compound of step 1, 24 g, 98.36 mmol) and potassium acetate (19.2 g, 196.72 mmol) in acetic anhydride (120 mL, 1200 mmol) were stirred for 3 hours at 120° C. The precipitate was filtered, washed with acetic acid and water and dried in vacuo to obtain the title compound. Yield: 15 g (64%); 1H NMR (DMSO-d6, 300 MHz): δ 13.142 (s, 1H), 9.32 (s, 1H), 8.159-8.166 (d, 1H, J=2.1 Hz), 7.822-7.859 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.734-7.763 (d, 1H, J=8.7 Hz); MS: m/z 225 (M+).
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][NH2:6].F[C:9]1[C:22]2C(=O)[C:20]3[CH:19]=[N+:18]([O-:24])[CH:17]=C[C:15]=3[C:14](=[O:25])[C:13]=2[C:12]([O:26][S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[CH:11][CH:10]=1>C1COCC1.O>[C:33]1([CH3:36])[CH:32]=[CH:31][C:30]([S:27]([O:26][C:12]2[CH:11]=[CH:10][C:9]3[NH:6][N:5]=[C:4]4[C:3]5[CH:17]=[N+:18]([O-:24])[CH:19]=[CH:20][C:15]=5[C:14](=[O:25])[C:13]=2[C:22]=34)(=[O:28])=[O:29])=[CH:35][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(F)c3c2C(=O)c2cc[n+]([O-])cc2C3=O)cc1
Reactant: CN(C)CCNN
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2ccc3[nH]nc4c3c2C(=O)c2cc[n+]([O-])cc2-4)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere a solution of N-[2-(dimethylamino)ethyl]hydrazine (0.805 g) in THF (10.75 mL) is added to a stirred suspension of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione-2-oxide of Preparative Example 21 (1.075 g) in THF (10.75 mL). After stirring for 2 h, the mixture is heated to 40° C. for 1 h. After cooling to room temperature the mixture is poured in water (150 mL) and the obtained suspension is stirred for 2 h. The precipitate is recovered by filtration and recrystallized from ethyl acetate/n-hexane to give 2-[2-(dimethylamino)ethyl)]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one-9-oxide (0.31 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:56]([CH:59]([CH3:61])[CH3:60])=[C:57]=[O:58].N(CC)=C=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH:59]([NH:56][C:57](=[O:58])[O:39][C@H:36]1[CH2:37][CH2:38][C@@H:33]([C:30]2[CH:31]=[CH:32][C:27]([C:23]3[N:22]=[C:21]4[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]5[CH2:15][O:14][C@@H:13]6[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]56)=[N:19][C:20]4=[CH:25][C:24]=3[Cl:26])=[CH:28][CH:29]=2)[CH2:34][CH2:35]1)([CH3:61])[CH3:60]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: CC(C)N=C=O
Agent: CCN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)O[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Reaction time: 12 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg), 4-dimethylamino-pyridine (DMAP, 1 mg) and triethylamine (30 μL) are dissolved in tetrahydrofurane (1 mL), treated with 2-isocyanatopropane (14 μL) and stirred for 12 hours. Triethylamine (60 μL) and isocyanatoethane (28 μL) are added and the mixture is stirred for 12 hours at 70° C. Again triethylamine (60 μL) and isocyanatoethane (28 μL) are added and the mixture is stirred for 12 hours at 70° C. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:23]([CH3:26])([CH3:25])[CH3:24])(=O)=O>C1(C)C=CC=CC=1>[CH3:24][Si:23]([N:1]([Si:23]([CH3:26])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(N)cn1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(c1ccc(C#N)nc1)[Si](C)(C)C
Yield: 63.5 %

Procedure:
About 6.17 g of 5-amino-2-pyridinecarbonitrile, 11.54 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 25.34 g of trimethylsilyl trifluoromethanesulfonate in 70 ml of toluene. The resulting mixture was heated to reflux for 2.5 hours and then evaporated under vacuum. The residue was extracted with 100 ml of hexane. The hexane layer was washed twice with saturated aqueous sodium bicarbonate solution (80 ml each time), dried with anhydrous sodium sulfate, and evaporated under vacuum, yielding 5-[bis(trimethylsilyl)amino]-2-pyridinecarbonitrile (BTMSAPyCN) as a green oil (8.67 g, 64% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 8.07 (doublet of doublets, 1H, aromatic proton), 6.70 (doublet of doublets, 1H, aromatic proton), 6.45 (doublet of doublets, 1H, aromatic proton), −0.16 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][CH2:19]O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[B-](F)(F)(F)[F:22].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:22][CH2:19][CH2:18][C:17]#[C:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[N:8]=[CH:9]2
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.9 %

Procedure:
To a solution of 4-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (1.0 g, 3.7 mmol; Intermediate 17) in dry dichloromethane (25 mL), was added triethylamine-3HF (1.2 g, 7.4 mmol). XtalFluor-E (1.2 g, 5.5 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether) affording the title compound (100 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.42 (dd, 1H), 5.86 (dd, 1H), 4.60 (dt, 2H), 3.88 (m, 1H), 3.78-3.71 (m, 1H), 2.89 (dt, 2H), 2.48-2.34 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.72 (m, 1H), 1.58 (m, 2H); LCMS: 273 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[CH:23][CH:22]=1)=[O:19].C(NC(C)C)(C)C>>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:18]([N:14]3[CH2:15][CH2:16][CH:11]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]4[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=4)[CH2:12][CH2:13]3)=[O:19])=[CH:22][CH:23]=2)=[N:29][CH:30]=1
Reactant: CN(CCc1ccncc1)C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CC(C)NC(C)C
Product: CN(CCc1ccncc1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from methyl-piperidine-4-yl-(2-pyridin-4-yl-ethyl)-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, preparative HPLC (method C) (15%, colourless oil). HPLC-MS m/z=501.4 (M+1), Rt: 2.04 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.[O:14]1[CH2:16][CH:15]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:16][CH:15]([OH:14])[CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:28])[CH3:27])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccccc1OCC1CO1
Reactant: Clc1ccc(NC2CCNC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)Nc1ccccc1OCC(O)CN1CCC(Nc2ccc(Cl)cc2)C1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 39.6 %

Procedure:
A mixture of N-(4-chlorophenyl)-3-pyrrolidinamine (2×CF3COOH), (186 mg, 0.438 mmol), N-[2-(2-oxiranylmethoxy)phenyl]acetamide (91 mg, 0.438 mmol) and K2CO3 (200 mg) in ethanol (6 mL) was kept on stirring at 65° C. for 2.5 h. The volatiles were removed in vacuo. The residue was partitioned between ethyl acetate and aq. NH4Cl solution. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0-3% MeOH in CHCl3) to give the titled product (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CCCCC=Nn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCNn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a mixture of 6-chloro-1-oxo-2-pentylidenamino-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (120 mg), acetic acid (76 μl) and methanol (5.0 ml) was added sodium cyano borohydride (80 mg) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with dichloromethane, and after drying, the organic layer was concentrated under reduced pressure. The residue was subjected to medium pressure preparative LC (hexane/ethyl acetate=9/1-1/1) to give the title compound (78 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH2:12])[C:3]=12.[CH3:13][O:14][C@H:15]([CH3:19])[C:16](O)=[O:17].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.C(OCC)(=O)C.O>[F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH:12][C:16](=[O:17])[C@H:15]([O:14][CH3:13])[CH3:19])[C:3]=12
Reactant: CO[C@H](C)C(=O)O
Reactant: Nc1c[nH]c2ncc(F)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(F)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
TEA (0.82 mL, 5.91 mmol) was added to a mixture of 4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 1.18 mmol; Example 13, Step C), (R)-2-methoxypropanoic acid (0.25 g, 2.37 mmol) and BOP-Cl (0.60 g, 2.37 mmol) in DCM (5 mL) at room temperature. The reaction was stirred at room temperature for 1 hour, and then a 2N LiOH solution (3 mL) was added. The mixture was stirred at room temperature for 30 minutes, and water (10 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by chromatography on silica gel (hexane:ethyl acetate 1:2) to give (R)—N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.21 g, 70%) as a solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>C(Cl)Cl.O1CCOCC1>[O:1]=[C:2]1[CH2:7][CH:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C(=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of the 1-tert-butyl 4-ethyl 2-oxopiperidine-1,4-dicarboxylate (20 g, 74.45 mmol) in DCM (93 mL) was add 4N hydrogen chloride in dioxane (30 mL). The reaction was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure. The resulting residue was dissolved in DCM and water, then adjusted to PH=8 with saturated aqueous Na2CO3 solution. The mixture was extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to afford ethyl 2-oxopiperidine-4-carboxylate (12 g, yield 94.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1.[S].[CH2:20]([NH2:23])[CH2:21][NH2:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[NH:22][CH2:21][CH2:20][N:23]=4)=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1
Reactant: NCCN
Reactant: ClCc1ccc(-c2nsc3ccc(Cl)cc23)cc1
Agent: [S]
Solvent: Cc1ccccc1
Product: Clc1ccc2snc(-c3ccc(C4=NCCN4)cc3)c2c1

Procedure:
44 g of 5-chloro-3-(4'-chloromethylphenyl)-1,2-benzisothiazole, 9.6 g of sulfur and 18 g of ethylenediamine in 500 ml of toluene are refluxed for 20 hours. The reaction mixture is filtered hot, the filtrate is cooled and the resulting crystals are filtered off. After recrystallization from toluene in the presence of active charcoal, 26 g of 5-chloro-3-[4-(imidazolin-2-yl)-phenyl]-1,2-benzisothiazole, melting at 195° C., are obtained. The yield corresponds to 55% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14](N)=[O:15].Cl.[C:21](=O)(O)[O-:22].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:22][CH3:21])=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(N)=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C

Procedure:
A mixture of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutyramide (1 mmol) and 4 ml of methanol, saturated with HCl gas, is heated at 75° for about 40 hours. The mixture is cooled, poured into saturated aqueous sodium bicarbonate and extracted with ether. The combined ether extracts are dried over sodium sulfate and solvent removed in vacuo to yield methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, which can be further purified by prep. thin layer chromatography.