Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:5])=[O:4].[CH2:12](Br)[C:13]#[CH:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O>[N+:3]([CH:6]=[C:7]1[NH:11][CH2:10][CH2:9][N:8]1[CH2:14][C:13]#[CH:12])([O-:5])=[O:4]
Reactant: O=[N+]([O-])C=C1NCCN1
Reactant: C#CCBr
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1CCNC1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
An ice-cooled mixture of 50 milliliters of dry dimethylformamide and 1.77 grams of a 57% by weight dispersion of sodium hydride in mineral oil, maintained under nitrogen atmosphere, was treated with 5.16 grams of 2-(nitromethylene)imidazolidine. After stirring for 1 hour, 7.97 grams of propargyl bromide was added. The mixture was stirred at 10° for an additional hour, allowed to warm to room temperature, and poured into 400 milliliters of saturated aqueous sodium sulfate. The product was extracted with three 300-milliliter portions of methylene chloride. The combined extract was dried with magnesium sulfate and the solvent was evaporated. Addition of ether to the residual oil gave a solid which was recrystallized from chloroform (charcoal) to give 3.1 grams of 3, as tan crystals, melting point: 146°-147°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](=[O:9])[N:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]=1[S-:16])#[N:2].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CCO>[CH2:23]([O:22][C:20]([C:19]1[S:16][C:4]2[N:5]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6](=[O:9])[CH:7]=[CH:8][C:3]=2[C:1]=1[NH2:2])=[O:21])[CH3:24]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1N

Procedure:
A mixture of Example 1 (0.34 g at 100%) and ethyl bromoacetate (0.197 mL) in EtOH (6 mL) was stirred at room temperature for 1 h. H2O (10 mL) was then added. The solid was filtered and washed with more H2O (2 mL). The product was dried under vacuum at 40° C. to constant weight to give the title compound as a pale pink solid (0.35 g). δH (DMSO-d6) 8.20 (1H, d, J 9.6 Hz), 7.60 (3H, m), 7.45 (2H, m), 7.15 (2H, br s), 6.55 (1H, d, J 9.6 Hz), 4.15 (2H, q, J 7.1 Hz), 1.20 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.29 minutes, 315 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:18]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH2:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:18]([O:25][C:26](=[O:30])[CH2:27][CH2:28][NH:29][C:3](=[O:4])[CH:2]([Br:1])[CH3:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(Br)C(=O)Cl
Reactant: NCCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)NCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
53.65 g (313 mmol) of 2-bromopropionic acid chloride is added in drops at 0° C. to 100 g (285 mmol) of β-alanine-benzyl ester-p-toluenesulfonic acid salt and 31.67 g (313 mmol) of triethylamine in 400 ml of methylene chloride. The temperature is not allowed to exceed 5° C. After addition is completed, it is stirred for 1 hour at 0° C., then for 2 hours at room temperature. 500 ml of ice water is added, and the water phase is set at pH 2 with 10% aqueous hydrochloric acid. The organic phase is separated, washed once each with 300 ml of 5% aqueous hydrochloric acid, 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from diisopropyl ethers
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:45])[C@@H:13]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3=[O:40])[C:29]=2[O:41][CH:42]([F:44])[F:43])(=[O:27])=[O:26])[CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-].Cl>C1COCC1.C(O)C.O.O>[Cl:23][C:20]1[S:19][C:18]([C:16]([NH:15][CH2:14][C@H:13]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][C:35]3=[O:40])[C:29]=2[O:41][CH:42]([F:44])[F:43])(=[O:26])=[O:27])[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[O:45])=[O:17])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1CCN(C(=O)[C@H](CNC(=O)c2ccc(Cl)s2)NS(=O)(=O)c2cccc(N3CCCCC3=O)c2OC(F)F)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC[C@H](NS(=O)(=O)c1cccc(N2CCCCC2=O)c1OC(F)F)C(=O)N1CCC(C(=O)O)CC1)c1ccc(Cl)s1
Reaction time: 2.5 h

Procedure:
The ethyl ester (1-{(S)-3-[(5-Chloro-thiophene-2-carbonyl)-amino]-2-[2-difluoromethoxy-3-(2-oxo-piperidin-1-yl)-benzenesulfonylamino]-propionyl}-piperidine-4-carboxylic acid ethyl ester) from example 9 (128 mg, 0.185 mmol) was treated with LiOH (222 μl, 0.555 mmol, 2.5 N in water) in THF/ethanol/water (2 ml, 1 ml, 0.5 ml). After 2.5 h the reaction was brought to pH=1-2 using 2 N HCl and further diluted with 30 ml water. The product crystallized from the aq layer and can be separated by filtration. Yield: 54 mg, 44%, colorless crystals.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[I:11]I.OO>O>[I:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: c1ccc2c(c1)CCCN2
Reactant: II
Agent: OO
Solvent: O
Product: Ic1ccc2c(c1)CCCN2
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a mixture of 1,2,3,4,-tetrahydroquinoline (0.34 g; 2.55 mmol) and I2 (0.32 g; 1.27 mmol) in H2O (10 ml), 30% H2O2 (0.26 ml; 2.55 mmol) was added at room temperature. The resulting mixture was vigorously stirred overnight at room temperature, and then extracted with Et2O (2×15 ml). The combined organic phase was washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; CH2Cl2), to give the title compound (0.33 g; 50%) as a creamy syrup. 1H-NMR (CDCl3) 1.84-1.92 (m, 2H); 2.69 (tr, 2H, J=6.4 Hz); 3.27 (tr, 2H, J=6.4 Hz); 3.82 (broad s, 1H); 6.22 (d, 1H, J=8.2 Hz); 7.15-7.21 (m, 2H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CS(C)=O>O>[C:5]([C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: C1CNCCN1
Reactant: N#Cc1cccc(F)c1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccc(N2CCNCC2)c1
Temperature: 100 °C
Yield: 143.1 %

Procedure:
A mixture of 3-fluorobenzonitrile (3.0 g, 25 mmol), piperazine (11.8 g, 137 mmol) and dimethylsulphoxide (20 ml) is heated at 100° C. for 48 hours under an atmosphere of nitrogen. The reaction mixture is then cooled, poured into water (200 ml) and the resultant precipitate collected. This solid is chromatographed on silica gel (dichloromethane) to give the title compound as a white solid (6.7 g). 1H NMR (DMSO, 500 MHz) δ7.15-7.40 (m, 4H), 3.28 (m, 3H), 3.12 (m, 1H), 2.80 (m, 1H), 2.59 (m, 3H).
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[O:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][C:20]=4[O:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1OC)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Yield: 89 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxy-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 89% of theory, C29H32N6O4 (528.6) Rf value: 0.13 (silica gel; dichloromethane/ethanol=4:1) ##EQU129##
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26]>>[CH2:18]([C:13]1[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:23][CH2:24][C:25]([OH:27])([CH3:28])[CH3:26])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)OC)cn1
Reactant: CC(C)(O)CN
Product: CCCCc1noc(C)c1/C=C/c1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 7 %

Procedure:
As described in example 10, 6-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (100 mg, 0.28 mmol), and 1-amino-2-methyl-propan-2-ol instead of DL-2-amino-1-propanol, was converted to the title compound (7.5 mg, 7%) which was obtained as a colorless solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 94:6). MS: m/e=364.4 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[N+:21]([O-])([OH:23])=[O:22]>>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[C:12]([N+:21]([O-:23])=[O:22])[CH:13]=[CH:14][CH:15]=2)[C:10]([S:17]([Cl:20])(=[O:18])=[O:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2ccccc12
Product: CC(=O)OCCc1ccc(S(=O)(=O)Cl)c2c([N+](=O)[O-])cccc12
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
4-(2-Acetoxy-ethyl)-naphthalene-1-sulfonyl chloride (76.96 g, 246 mmol) was added portionwise over 12 minutes to 90% nitric acid (154 mL, 3.278 mol) cooled in an ice-methanol bath (−20° C.). After the addition was complete, the reaction mixture was stirred at −20° C. for an additional 15 minutes. The reaction mixture was partitioned between ice water (800 mL) and chloroform (800 mL). The aqueous layer was extracted with chloroform (100 mL). The combined organic layers were washed with brine (400 mL, 200 mL), then dried over magnesium sulfate, filtered, and evaporated to a golden oil. Diethyl ether (300 mL) was added to the crude product and the mixture was shaken vigorously to afford an off-white solid. The solid was collected by filtration, washed with ether (2×50 mL), and dried under vacuum to afford 4-(2-acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride (41.85 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 96 h
Yield: 57 %

Procedure:
A solution of 1.0 g (0.0025 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 20 ml of tetrahydrofuran was treated with 5 ml (0.037 mol) of dipropylamine and stirred at 50° for 96 hrs. All volatiles were removed in a waterjet vacuum and the residue was taken up with ethyl acetate and water. The organic phase was dried over magnesium sulphate, concentrated and the residue remaining was chromatographed over silica gel with methylene chloride/methanol 95:5 as the eluent. After recrystallization from ethyl acetate there was obtained 0.67 g (58%) of (S)-8-chloro-1-(4-dipropylaminomethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 213-214° and [α]D20 =-68.5° (MeOH, c=0.8%).
Reaction SMILES: [N:1]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][N:2]=1.N1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]CCCN1>>[NH2:2][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([NH2:1])[CH:20]([CH2:19][CH3:18])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:5]([CH2:4][CH3:3])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C1=CCCN=NCCC=CCC1
Reactant: C1CCCCCNNCCCC1
Product: CCCCC(CC)C(N)CCCCCCCCC(N)C(CC)CCCC

Procedure:
The 1,2-diaza-1,5,9-cyclododecatriene and 1,2-diazacyclododecane, used as starting products, can be produced by the methods described in the German Offenlegungsschriften Nos. 2,330,087 and 2,549,403.
Reaction SMILES: [O:1]1[C@H:3]([CH2:4][OH:5])[C@@H:2]1[CH2:6][OH:7].C(OCC)(=O)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(N(CC)CC)C>[CH3:14][S:15]([O:7][CH2:6][C@H:2]1[C@@H:3]([CH2:4][O:5][S:15]([CH3:14])(=[O:17])=[O:16])[O:1]1)(=[O:17])=[O:16]
Reactant: OC[C@@H]1O[C@@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1O[C@@H]1COS(C)(=O)=O
Reaction time: 4 h

Procedure:
To a mixture of 2.3 g of cis-oxirane-2,3-dimethanol and 200 ml of ethyl acetate was added 9.3 ml of triethylamine and then 4.3 ml of methanesulfonyl chloride under ice-cooling, followed by stirring at the same temperature for 4 hours. The reaction mixture was filtered through silica gel and washed with ethyl acetate. Thereafter, the filtrate was evaporated, to give 5.4 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].[C:22]([C:26]1[CH:41]=[CH:40][C:29]([CH2:30][NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:22]([C:26]1[CH:41]=[CH:40][C:29]([CH2:30][N:31]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)[C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=2)=[CH:28][CH:27]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(CNCc2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(C(C)(C)C)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) in methylene chloride (30 mL) were added N-(4-tert-butylbenzyl)-N-(4-chlorobenzyl)amine (1.04 g, 3.60 mmol), N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Twice repeated purification on prepacked columns of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 0.459 g (27%) of a whitish oil.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].C(N(C(C)C)C(C)C)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C[C@@H](N)CO
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
(2R)-2-Aminopropan-1-ol (2.0 g, 26.7 mmol) and N-ethyl-N,N-diisopropylamine (8.5 mL, 48.9 mmol) was added dropwise over 20 min to a cooled (0° C.) solution of 4-bromobenzenesulfonyl chloride (6.12 g, 24 mmol) in methylene chloride (20 mL). The reaction mixture was allowed to stir for 1 h. Water was added and the mixture was washed, twice, with HCl (aq, 1 M) and one time with saturated aqueous sodium hydrogen carbonate. The organic phase was dried over sodium sulfate and evaporated to give 6.8 g, (96% yield) of the title compound: 1H NMR (CD3OD, 400 MHz) δ 7.82 (d, J=8 Hz, 2H), 7.76 (d, J=8 Hz, 2H), 3.44 (m, 1H), 3.34 (m, 3H), 1.03 (d, J=7 Hz, 3H); MS (ESI) m/z (M++1); 13C NMR (CD3OD, 100 MHz) 142.42, 133.36, 129.74, 127.90, 66.81, 52.49, 17.94
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[C:9]([C:13]1[CH:14]=[CH:15][C:16]([S:19][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[NH2:4])=[CH:17][CH:18]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: Nc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)c1ccc(Sc2ccccc2N)cc1
Yield: 89.7 %

Procedure:
The general procedure in example 39 was followed. 2-Iodoaniline (219 mg, 1.0 mmol), 4-tert-butylthiophenol (166 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-propanol (1.0 mL) were used to obtain the 2-(4-tert-butylphenyl)sulfanylaniline (231 mg, 90% yield) as light yellow liquid. Column chromatographic solvent (hexane/ethyl acetate=20/1). Rf=0.4 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 7.42 (dd, 1 H, J=1.5 Hz, 7.5 Hz), 7.17-7.24 (m, 4 H), 7.00 (dt, 2 H, J=1.8 Hz, 8.4 Hz), 6.70-6.78 (m, 2 H), 4.28 (brs, 2 H), 1.26 (s, 9 H). 13C NMR (CDCl3, 75 MHz) δ 148.8, 148.7, 137.5, 133.3, 131.1, 126.5, 126.3, 118.9, 115.5, 115.0, 34.8, 31.7. IR (neat, cm−1) 3471, 3375, 3072, 3062, 3020, 2962, 2902, 2867. MS (EI) m/z (relative intensity) 257 (70), 242 (100). Anal. Cald. for C16H19NS, Cald. C, 74.66; H, 7.44. Found C, 74.64; H, 7.30.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Cl[CH:5]([CH:11]=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CC(C)=O>[S:2]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:3]=[CH:1]1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: NC=S
Solvent: CC(C)=O
Product: CCOC(=O)c1cncs1
Yield: 60 %

Procedure:
To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl 2-chloro-2-formylacetate. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf =0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:23])[CH2:21][CH3:22])=[C:13]3[NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][CH2:34][CH:33]([NH:37]C(=O)OC(C)(C)C)[CH2:32]3)=[N:29][CH:30]=2)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].Cl>ClCCl.C(OCC)C>[NH2:37][CH:33]1[CH2:34][CH2:35][CH2:36][N:31]([C:28]2[N:29]=[CH:30][C:25]([NH:24][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:5]=[C:6]([F:9])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=5)[CH:11]=4)[N:16]=[CH:15][C:14]=3[C:20](=[O:23])[CH2:21][CH3:22])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
tert-butyl 1-(5-(6-(3-chloro-5-fluoro-4-hydroxyphenyl)-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (32 mg, 0.051 mmol) was dissolved in dichloromethane (5 mL). To this solution was added a 2.0 M HCl solution in diethyl ether (2 mL) the mixture was stirred for 16 h at room temperature where a precipitate formed. The precipitate was filtered off, washed with dichloromethane (10 mL), dried under vacuum to obtain the desired product as the HCl salt (16 mg, 49%) as an orange solid: 1H NMR (500 MHz, MeOD) δ 9.28 (s, 1H), 8.23 (m, 2H), 8.01 (m, 2H), 7.75 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.10 (t, J=4.9 Hz, 2H), 4.54 (s, 1H), 4.04 (d, J=13.0 Hz, 1H), 3.36 (m, 3H), 3.24 (q, J=13.3, 6.2 Hz, 1H), 2.20 (m, 1H), 1.97 (m, 1H), 1.74 (m, 2H), 1.26 (t, J=6.6 Hz, 3H); ESI MS m/z 520, [C28H27ClFN5O2+H]+; HPLC 98.7% (AUC), tR=10.05 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[CH2:48]([S:50](Cl)(=[O:52])=[O:51])[CH3:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([S:50]([CH2:48][CH3:49])(=[O:52])=[O:51])[CH2:42][CH2:41]1
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A42, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and ethanesulfonyl chloride as starting materials in 41% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.40 (s, 1H), 9.36 (s, 1H), 9.28 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H), 7.21 (d, 1H), 7.04 (m, 2H), 6.87 (d, 1H), 6.78 (d, 1H), 3.60 (m, 2H), 3.01 (m, 2H), 2.83 (m, 6H), 2.27 (m, 2H), 1.91 (m, 1H), 1.78 (m, 2H), 1.22 (m, 2H), 1.20 (m, 3H). LCMS for C27H32ClN6O3S (M+H)+: m/z=555.2.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:12]3[CH:19]=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(OC1CC=CC1)(=O)=O>CN(C)C=O>[CH:23]1([N:17]2[C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][C@@H:1]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[CH2:3][CH2:2]4)[C:12]=3[CH:19]=[CH:18]2)[CH2:24][CH:25]=[CH:20][CH2:26]1
Reactant: Cc1ccccc1
Reactant: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2[nH]ccc12
Agent: CS(=O)(=O)OC1CC=CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C1=CCC(n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N-[(1S)-2,3-Dihydro-1H-inden-1-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.32 g, 5.29 mmol) was azeotroped with toluene and placed under high vacuum for 30 min. N,N-Dimethylformamide (17.7 mL) was added, followed by cesium carbonate (1.99 g, 6.10 mmol). The mixture was stirred at 70° C. for 10 min. Cyclopent-3-en-1-yl methanesulfonate (0.660 g, 4.07 mmol) in N,N-dimethylformamide (12.6 mL) was added dropwise. The reaction mixture was heated to 110° C. for 1 h. The reaction mixture was cooled, quenched with brine and diluted with H2O. The aqueous layer was extracted with EtOAc (3×), washed with H2O and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by via silica gel chromatography, eluting with a gradient of 0 to 5% MeOH in DCM followed by 25 to 50% EtOAc in hexanes, to afford the title compound as a pale brown solid (0.684 g, 53%). LC/MS: Rt=1.38 min, ES+ 317 (FA standard).