Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.[Cl:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2([C:37](=N)OCC)[CH2:36][CH2:35]2)[CH:33]=1.C(N(CC)CC)C>C(O)C>[Cl:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2([C:37]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH2:36][CH2:35]2)[CH:33]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2cc(Cl)cn2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC(=O)O
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(n5cc(Cl)cn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (5.5 g, 15.2 mmol) and acetic acid (17.4 mL, 305 mmol) in ethanol (20 mL) was added a solution of ethyl 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbimidate (3.25 g, 15.2 mmol) in ethanol (30 mL) followed by triethylamine (12.7 mL, 91.2 mmol). The resulting mixture was purged with nitrogen. The reaction mixture was stirred for 18 h at 100° C. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between a saturated aqueous solution of ammonium chloride (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted with dichloromethane (50 mL). The combined organics were washed with a saturated aqueous solution of sodium bicarbonate and the resulting aqueous layer was extracted with dichloromethane (50 mL). The organics were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-5% methanol in dichloromethane) to afford (R)-(1-(2-(1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (6.33 g, 94%). 1H NMR (500 MHz, CDCl3) δ 1.55-1.70 (m, 1H), 1.72-2.05 (m, 11H), 2.60-2.70 (m, 1H), 2.90-2.95 (m, 1H), 3.03-3.10 (m, 1H), 3.42-3.50 (m, 3H), 3.56-3.62 (m, 1H), 4.20-4.25 (m, 1H), 4.38-4.44 (m, 1H), 6.62-6.68 (m, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.66-7.72 (m, 1H); MS (ES+) (M+H) 440; UPLC retention time 0.47 min (Method N).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].O1CCCC1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]([CH2:23][CH2:24][NH2:25])[CH2:16][CH2:15]2.C(N(CC)CC)C>O>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[CH:17]([CH2:23][CH2:24][NH:25][C:1](=[O:4])[CH2:2][CH3:3])[CH2:16][CH2:15]2
Reactant: CCC(=O)Cl
Reactant: COc1cc2c(cc1F)CCC2CCN
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)NCCC1CCc2cc(F)c(OC)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
Propionyl chloride (2.5 g, 27.0 mmols) was gradually and dropwise added to a tetrahydrofuran (20 ml) solution containing 2-(5-fluoro-6-methoxyindan-1-yl)ethylamine (4.35 g, 20.8 mmols) and triethylamine (4.21 g, 41.6 mmols) while cooling with ice. After having been stirred at room temperature for 2 hours, the reaction mixture was poured into water, and the organic substance was extracted out with ethyl acetate. The extract was washed with a saturated saline solution and water and then dried with anhydrous magnesium sulfate, and the solvent was removed through distillation under reduced pressure. The resulting residue was purified through silica-gel column chromatography (ethyl acetate/hexane=90/10) to obtain 4.87 g (yield: 88%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=O.OC1C=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[CH:21]=[CH:20][C:19]([C:30]([F:33])([F:32])[F:31])=[C:15]2[CH2:14][O:13][C:11]2[CH:10]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:19]([C:30]([F:31])([F:32])[F:33])[CH:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)CCc1ccc(O)cc1C(F)(F)F
Reactant: Nc1cccc(F)c1
Product: O=C(O)CCc1ccc(OCc2c(C(F)(F)F)ccn2-c2cccc(F)c2)cc1C(F)(F)F

Procedure:
3-Fluoroaniline was reacted with ethyl bromoacetate according to the procedure of Example 73, Step A. The resulting product was then reacted according to the procedures of Example 73, Steps B and C and Example 1, Step D, in sequence. The resulting product was then reacted with ethyl 3-(4-hydroxy-2-trifluoromethylphenyl)propanoate according to the procedures of Example 1, Step E and Step F, in sequence, to yield the title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[O:9].C([O-])([O-])=O.[Na+].[Na+].[CH3:16][C:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O.ClCCl>[CH3:16][C:17]1([C:23]([NH:2][C@H:3]2[CH2:8][CH2:7][CH2:6][NH:5][C:4]2=[O:9])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: N[C@H]1CCCNC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C(=O)N[C@H]2CCCNC2=O)CCCCC1
Reaction time: 18 h
Yield: 41.7 %

Procedure:
(S)-3-Amino-tetrahydropyridin-2-one hydrochloride (2 mmol) and Na2CO3 (6 mmol) in water (25 ml) were added to a solution of 1-methylcyclohexanecarbonyl chloride (2 mmol) in dichloromethane (25 ml) at ambient temperature and the reaction was stirred for 18 hours. The organic layer was then separated and the aqueous phase was extracted with additional dichloromethane. The combined organic layers were dried over Na2SO4 and reduced in vacuo. The residue was purified by silica column chromatography (EtOAc:hexanes 1:3 to MeOH:EtOAc 1:19) to give as an amorphous solid (199 mg, 42%); νmax/cm−1 3335, 3269 (NH), 1650, 1621 (CO), 1529 (NH); δH (500 MHz, CDCl3) 6.65 (1H, br d, J5, NH), 6.59 (1H, br s, NH), 4.18 (1H, dt, J 11.5, 5.5, CHNH), 3.30 (2H, td, J6.5, 2.5, CH2NH), 2.52 (1H, ddt, J 13, 5.5, 4.5, lactam CH2), 1.92-1.83 (4H, m, 2× lactam CH and 2× cyclohexane CH2), 1.55-1.23 (9H, m, lactam CH and 8× cyclohexane CH2) and 1.11 (3H, s, CH3); δC (125 MHz, CDCl3) 178.0, 172.3 (CO), 50.4 (NHCHCO), 42.6 (CH3C quat), 41.5, 35.6, 35.5, 27.0 (CH2), 26.3 (CH3), 25.7, 22.8 (×2), 20.9 (CH2); m/z (MNa+C13H22N2O2Na requires 261.1579) 261.1570.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1)[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH2:9][CH2:8]1.[CH3:30][N:31]([S:53]([CH3:56])(=[O:55])=[O:54])[C:32]1[CH:33]=[C:34]([C:50](O)=[O:51])[C:35]2[CH2:36][CH2:37][N:38]([CH:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][CH3:46])[C:39](=[O:42])[C:40]=2[CH:41]=1.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl.O>[F:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=1)[CH2:21][C@H:3]([NH:2][C:50]([C:34]1[C:35]2[CH2:36][CH2:37][N:38]([CH:43]([CH2:47][CH2:48][CH3:49])[CH2:44][CH2:45][CH3:46])[C:39](=[O:42])[C:40]=2[CH:41]=[C:32]([N:31]([CH3:30])[S:53]([CH3:56])(=[O:55])=[O:54])[CH:33]=1)=[O:51])[C@H:4]([OH:20])[CH2:5][NH:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)[CH2:9][CH2:8]1
Reactant: CCCC(CCC)N1CCc2c(C(=O)O)cc(N(C)S(C)(=O)=O)cc2C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(CCC)N1CCc2c(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNC3(c4cccc(C(F)(F)F)c4)CC3)cc(N(C)S(C)(=O)=O)cc2C1=O
Reaction time: 20 h
Yield: 79.4 %

Procedure:
Poured into a suspension of 233 mg of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1), 278 mg of 7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid, 12 mg of hydroxybenzotriazole and 142 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 cm3 of dichloromethane is 0.4 cm3 of N,N-diisopropylethylamine at a temperature close to 20° C. The solution is kept stirring for 20 h at a temperature close to 20° C. 20 cm3 of water are added to the reaction medium. After decanting, the organic phase is filtered through a pellet of 15 g of 40-63 μm silica. The silica pellet is washed firstly with 150 cm3 of dichloromethane then secondly with 150 cm3 of a mixture of 50% ethyl acetate/50% dichloromethane. This second filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). 330 mg of N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]-7-[methyl(methylsulfonyl)amino]-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide are obtained in the form of a white foam.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[C:17]1([Mg]Cl)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (23.56 g, 105 mmol) in absol. THF (100 ml) was added dropwise to a 25 percent strength solution of phenylmagnesium chloride (144 ml, 262.5 mmol) in THF under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8](O)[CH2:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7]2[CH:8]=[CH:9][CH2:10][CH2:11][C:12]([CH3:14])([CH3:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CCCC(O)c2c(Br)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCC=Cc2c(Br)cccc21
Temperature: 25 °C

Procedure:
A solution of 4-bromo-9,9-dimethyl-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol (4.402 g, 16.35 mmol) and p-toluenesulfonic acid monohydrate (0.31 g, 1.64 mmol) in toluene (80 ml) was heated under reflux in a reaction vessel equipped with a Dean-Stark trap under dehydrating conditions for 0.5 hr. After the reaction solution was cooled to room temperature, the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane) to give the objective substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Br[CH:11]1[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([O:8][CH:11]2[CH2:13][CH2:12]2)[CH:7]=1
Reactant: Oc1cc(Br)ccc1Cl
Reactant: BrC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc(Br)cc1OC1CC1
Temperature: 150 °C
Reaction time: 47 h
Yield: 87.9 %

Procedure:
A mixture of 5-bromo-2-chlorophenol (543 mg, 2.62 mmol), bromocyclopropane (836 μl, 10.47 mmol) and caesium carbonate (1.701 g, 5.24 mmol) in N,N-dimethylacetamide (7.5 ml) was stirred for 47 h at 150° C. After 25.25 h further bromocyclopropane (836 μl, 10.47 mmol) was added. The reaction mixture was poured onto ice-water (40 ml) and set to pH=2 with aqueous HCl (1 N, 9.5 ml). This mixture was extracted with TBME (twice 50 ml). The organic layers were washed with brine (40 ml), combined and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 67:33) afforded the title compound (570 mg, 87%) as a light yellow oil. MS m/e: 248.0 [M+H]+
Reaction SMILES: [Cl-].[CH:2]1([CH2:12][CH2:13]O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.Cl.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCCC1.N1C=CC=CC=1>[CH:2]1([CH2:12][CH2:13][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1
Reactant: OCCC1OCCc2ccccc21
Reactant: C1CNCCN1
Agent: Cl
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCOC2CCN1CCNCC1
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Methanesulfony chloride (524 ml, 6.77 mol) is added to a cooled mixture of (-)-2-(isochroman-1-yl)ethanol (EXAMPLE 48, LXXIX, 940 g, 5.2 mol), diisopropylethylamine (1.27 1, 7.29 mol) in tetrahydrofuran (5.6 l). After 4 hr, aqueous hydrochloric acid (1N, 8 l) is added and the mixture extracted with ethyl acetate (17 1). The organic phase is washed with saturated aqueous sodium chloride (2 l) and concentrated under reduced pressure. The concentrate is dissolved in pyridine (4 l) and added to a mixture of piperazine (2.71 kg, 31.5 mol) in pyridine (6.88 l). After 21 hr, the mixture is concentrated under reduced pressure to a slurry and the solids filtered off and washed with ethyl acetate (10 l). The filtrate is concentrated under reduced pressure to an oil and azeotroped with heptane (8 l). The oil is dissolved in ethyl acetate (20 l) and washed with saturated aqueous sodium bicarbonate (2.4 l). The organic phase is concentrated under reduced pressure and the oil azeotroped with toluene (4 l) to give 1.28 kg of the title compound; HPLC retention time=7.3 min (Column=Zorbax C-8; Injection vol.=10 μl; Mobile phase=water (1100 ml)/acetonitrile (500 ml)/methanol (400 mm)/potassium phosphate, monobasic (15 g); Detector=254 nm; Flow rate=0.5 ml/min).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[CH3:3].C(O)(C)(C)C.[C:10]([O:14][OH:15])([CH3:13])([CH3:12])[CH3:11]>O>[C:2]([O:15][O:14][C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)C
Reactant: CC(C)(C)OO
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OOC(C)(C)C

Procedure:
In accordance with the invention, isobutane oxidate comprised of both tertiary butyl alcohol and tertiary butyl hydroperoxide is reacted in the presence of a water soluble acid catalyst under conditions effective to form ditertiary butyl peroxide. The reaction mixture is phase separated in order to separately recover an aqueous phase containing tertiary butyl alcohol and the acid catalyst and an organic phase containing ditertiary butyl peroxide. The aqueous phase is distilled in order to recover tertiary butyl alcohol overhead and also to separate any water produced during the reaction or introduced in the reaction feed streams, and a concentrated aqueous acid stream is recovered and recycled to the peroxide-forming reaction. The organic phase containing product ditertiary butyl peroxide is then subjected to a series of separation steps including a water extraction step in order to recover product ditertiary butyl peroxide as well as such tertiary butyl alcohol as is contained in the organic phase.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=O)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)[CH3:15].[OH-].[K+].CC[OH:27]>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:8]([OH:12])=[O:27])=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9]2)=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCO
Reactant: COc1ccc2c(c1)NC(=O)C2=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(C(=O)O)cc(-c3ccccc3)nc2c1

Procedure:
5 g (28.2 mmol) of 6-methoxyisatin, 4 ml (33.8 mmol) of acetophenone and 5.2 g (92.6 mmol) of potassium hydroxide were dissolved in 22.9 ml of abs. EtOH and the slurry heated at 80° C. for 42 hours. After cooling of the reaction mixture, 50 ml of water were added and the solution extracted with 50 ml of Et2O. The ice-cooled aqueous phase was acidified to pH 1 with 37% HCl and the precipitate collected by filtration and washed with water.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29]([F:34])=[N:30][NH:31]5)=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:45](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29]([F:34])=[N:30][N:31]5[CH3:45])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(F)n[nH]c5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(F)nn(C)c5c4)c3)sc2c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(3-fluoro-1H-indazol-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (39.7 mg, 0.0631 mmol) and cesium carbonate (62 mg, 0.189 mmol) in anhydrous DMF (1.0 mL) at 0° C. was added iodomethane (5.9 μL, 0.0947 mmol) and reaction stirred for 1 h. More iodomethane (3.0 μL) was added and reaction was stirred for 30 minutes, and stored in freezer overnight. Reaction mixture was diluted with ethyl acetate, washed with 5% lithium chloride solution (3×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C35H33ClFN4O3S: 643.2 (M+H+); Found: 643.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: CO
Reactant: COc1ccc(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 3-hydroxy-4-(methyloxy)benzoic acid (25 g, 149 mmol.) in methanol (200 mL) was added concentrated sulfuric acid (1 mL) and the mixture was brought to reflux over 18 hours. The resulting homogeneous solution was cooled to room temperature, concentrated in vacuo and the residual oil taken into ethyl acetate (300 mL). The solution was washed once with water, saturated aqueous sodium hydrogencarbonate then brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave methyl 3-hydroxy-4-(methyloxy)benzoate (27 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3): 7.59 (dd, 1H), 7.57 (d, 1H), 6.85 (d, 1H), 5.72 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[CH2:8]1[C:14]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:13]=2[CH2:12][CH2:11][NH:10][CH2:9]1.C(N(CC)CC)C>CO>[CH3:1][N:2]([CH3:6])[C:3]([N:10]1[CH2:9][CH2:8][C:14]2[CH:15]=[CH:16][C:17]([S:19]([NH2:22])(=[O:20])=[O:21])=[CH:18][C:13]=2[CH2:12][CH2:11]1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: NS(=O)(=O)c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CN(C)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Temperature: 25 °C

Procedure:
8.05 Ml. of dimethylcarbamoyl chloride are added dropwise while cooling at about 25° C. in the course of 3 minutes to a solution of 21.5 g. of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride and 24.5 ml. of triethylamine in 400 ml. of methanol and the mixture is subsequently stirred for a further 15 hours, during which a crystalline precipitate results. By evaporation of the solvent in vacuo and digestion and washing of the crystalline evaporation residue with water, there is obtained 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide, m.p. 192°-193° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:16]([F:24])[CH:15]=2)=[CH:4][CH:3]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])(O)=O.[Na+]>COCCOC.O>[F:24][C:16]1[CH:15]=[C:14]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[CH:3][CH:4]=3)[C:12]([CH3:13])=[CH:11][CH:10]=2)[CH:19]=[CH:18][C:17]=1[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: OB(O)c1ccco1
Reactant: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)c(F)c2)n1-c1ccc(-c2ccco2)cc1
Yield: 60.7 %

Procedure:
To a stirred suspension of 1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-5-methyl-1H-pyrrole (0.41 g, 1 mmol), 2-furanboronic acid (0.14 g, 1.26 mmol), NaHCO3 (0.19 g, 2.3 mmol) in DME-water (6 mL-2 mL) was added dichlorobis(triphenylphosphine) palladium (80 mg, 0.115 mmol) at room temperature under nitrogen. The mixture was heated at reflux temperature for 6 hours. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to give the title compound (0.24 g, 61% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][NH:14][CH:13]=1)=[O:11])[CH3:8].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.O>CS(C)=O>[CH2:7]([O:9][C:10]([C:12]1[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][N:14]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:11])[CH3:8]
Reactant: Clc1ccnc2ccccc12
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(-c2ccnc3ccccc23)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added to 1.036 g (5 mmol) of 3-ethoxycarbonyl-4-trifluoromethyl-1H-pyrrole and 0.82 g (5 mmol) of 4-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 18 hours at a temperature in the region of 110° C., the reaction mixture is poured into 30 mL of water and then left to crystallize for 1 hour at 20° C. After the solid residue has been filtered off and air-dried, 1.48 g of 3-ethoxycarbonyl-4-trifluoromethyl-1-(quinolin-4-yl)-1H-pyrrole are obtained in the form of beige-colored crystals melting at 108° C. IR spectrum (KBr): 3139; 1718; 1564; 1537; 1511; 1306; 1281; 1249; 1169; 1146; 1123; 1036; 846 and 773 cm1.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[C:18]3[C:17](=[O:19])[N:15]([CH3:16])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=3[N:11]=[CH:10]2)[N:4]=1.C(N)(=O)C1C(=CC=CC=1)C([NH2:27])=O.[K]>CN(C)C=O>[ClH:1].[NH2:27][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][N:9]2[C:18]3[C:17](=[O:19])[N:15]([CH3:16])[C:14](=[O:20])[N:13]([CH3:21])[C:12]=3[N:11]=[CH:10]2)[N:4]=1
Reactant: Cn1c(=O)c2c(ncn2Cc2noc(CCl)n2)n(C)c1=O
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: [K]
Solvent: CN(C)C=O
Product: Cl
Product: Cn1c(=O)c2c(ncn2Cc2noc(CN)n2)n(C)c1=O
Yield: 74.2 %

Procedure:
30.9 g. 7-[(5-chloromethyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are heated in 300 cm3 dimethylformamide with 18.5 g. potassium phthalamide under stirring for 6 hours. Dimethylformamide is distilled off at reduced pressure, and the residue is triturated with 300 cm3 ethanol and 5.2 g. of hydrazine hydrate are added, the mixture is heated on water bath for 2 hours, acidified with concentrated aqueous hydrochloric acid, the mixture is boiled and filtered when hot and the filtrate is evaporated. After crystallization from methanol 24.7 g. (74.2% yield) of 7-[(5-aminomethyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline-hydrochloride are obtained, m.p.: 204°-207° C.