Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[C:12]1(B(O)O)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:12]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OB(O)C1=CCCCC1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(C2=CCCCC2)n1
Yield: 61 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and cyclohexenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.15 equiv.) to give 6-cyclohexenyl-5-fluoropicolinic acid in 61% yield. LC/MS=222.0 (M+H), Rt=0.52 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][OH:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14].[Cl:18]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([Cl:18])=[N:11][OH:12])=[CH:6][C:5]=1[C:13]([F:15])([F:14])[F:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(C=NO)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(C(Cl)=NO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 94.7 %

Procedure:
To a solution of 4-(hydroxyimino-methyl)-2-trifluoromethyl-benzoic acid methyl ester (Example I11) (3.90 g) in N,N-dimethylformamide (20 ml) was added N-chlorosuccinimide (“NCS”) (2.318 g). The reaction mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was poured into water (400 ml). The solids were isolated by filtration and dried to give 4-(chloro(hydroxyimino)methyl)-2-trifluoromethyl-benzoic acid methyl ester (4.21 g) as an off-white powder. 1H-NMR (CDCl3, 400 MHz): 9.00 (s, 1H), 8.24-8.04 (m, 3H), 3.96 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][F:42])(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[F:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)[nH]c1cc(OCCOCCOCCF)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To tert-butyl 7-hydroxy-9H-carbazol-2-ylcarbamate (165 mg, 0.55 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (202 mg, 0.66 mmol) in 2 mL of NMP was added Cs2CO3 (179 mg, 0.55 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with water (3×50 mL) and dried over MgSO4. After solvent removal, the residue was chromatographed (hexane/EtOAc) to afford tert-butyl 7-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)-9H-carbazol-2-ylcarbamate as a white solid (130 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.83-7.79 (m, 3H), 6.91 (d, J=2.0 Hz, 1H), 6.86 (dd, J=8.4, 2.0 Hz, 1H), 6.83 (dd, J=8.8, 2.4 Hz, 1H), 6.63 (s, 1H), 4.64 (m, 1H), 4.51 (m, 1 H), 4.21 (m, 2H), 3.91 (m, 2H), 3.81-3.71 (m, 6H), 1.55 (s, 9H); MS (ESI) m/z 433 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1sc(Cl)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(Oc2ccc(Cl)cc2Cl)nc1C
Yield: 58.2 %

Procedure:
A mixture of 6.24 g (0.03 mole) of ethyl 2-chloro-4-methyl-5-thiazolecarboxylate, 4.89 g (0.03 mole) of 2,4-dichlorophenol, 4.14 g (0.03 mole) of potassium carbonate and 40 ml. of acetone was held at reflux for 89 hours. Acetone was removed under reduced pressure. The residue was treated with 50 ml. of water and extracted with ether. The ether solution was washed successively with saturated sodium bicarbonate, 30 ml. of 10% sodium hydroxide and 50 ml. of water. The ether solution was dried (MgSO4) and concentrated. The residue was recrystallized from hexane to give 5.8 g (58%) of ethyl 2-(2',4'-dichlorophenoxy)-4-methyl-5-thiazolecarboxylate as a white solid, m.p. 71°-73° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[CH:15]=[C:14]([NH:17][C:18]4[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=4)[N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=CC=1.FC(F)(F)C(O)=[O:31]>>[NH:8]1[C:16]2[CH:15]=[C:14]([NH:17][C:18]3[N:19]=[CH:20][C:21]([C:24]([NH2:25])=[O:31])=[N:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2cnc3cnc(Nc4cnc(C#N)cn4)cc32)cc1
Product: NC(=O)c1cnc(Nc2cc3[nH]cnc3cn2)cn1
Yield: 8 %

Procedure:
5-(1-(4-Methoxybenzyl)-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbo-nitrile (0.16 mmol) was treated overnight with trifluoroacetic acid at 80° C. The solution was evaporated to dryness and the residue was purified using preparative HPLC to give the title compound (3.23 mg, 8%). 1H NMR (d6-DMSO, 400 MHz) δ 12.68 (br s, 1H), 10.46 (br s, 1H), 8.76 (d, 1H, J=1.2 Hz), 8.72 (d, 2H, =1.2 Hz), 8.28 (br s, 2H), 7.90 (s, 1H), 7.51 (s, 1H). LCMS (2) Rt=1.02 min; m/z (ESI+) 256 (MH+), (ESI−) 254 (M−H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4](S(C)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([F:20])[C:11]=2[F:21])=[O:9])=[CH:6][N:5]=[C:4]([NH:42][CH:39]2[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: COc1cc(F)c(F)c(C(=O)c2cnc(S(C)=O)nc2N)c1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(F)c(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c1OC

Procedure:
The compound was prepared from (4-amino-2-methylsulfinyl-pyrimidin-5-yl)-(2,3-difluoro-5,6-dimethoxy-phenyl)-methanone (Example 260) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) in an analogous manner as described in Example 172. HR-MS (ES, m/z) calculated for C19H24N5O5SF [(M+H)+] 472.1465, observed 472.1461.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[CH:20]=[CH:19][C:18]2[C:17](=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:22])[C:9]=2[CH:8]=1>O1CCCC1>[Br:2][CH2:6][C:7]1[CH:20]=[CH:19][C:18]2[C:17](=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:22])[C:9]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: O=C1c2ccccc2C(=O)c2cc(CO)ccc21
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of PBr3 (82 mg, 302 μmole) in 5 mL of tetrahydrofuran (THF) was placed in ice bath. 2-Hydroxymethylanthraquinone (100 mg, 421 μmole) obtained from Aldrich Chemical Co., St. Louis, Miss., in 10 mL of THF was added to the mixture slowly over 10 minutes. After 1 hour at 0° C., the reaction temperature was raised to room temperature and the mixture was stirred for 48 hours. The mixture was evaporated and then redissolved in ethyl acetate for H2O extraction. The organic layer was dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. 2-Bromomethylanthraquinone was purified by flash silica column chromatography (Yield=52%). 1H NMR (300 MHz, CDCl3) δ 8.24 (2H, m), 8.14 (1H, s), 8.01(1H,d), 7.70 (1H, d), 7.57 (2H, m), 4.68 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH2:44])[CH2:37][CH2:38][CH3:39]>C1COCC1>[CH2:36]([N:40]([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][NH:44][C:16]1[N:17]=[C:18]([C:19]2[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]2[CH2:12][NH:11][C:10](=[O:35])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1)[CH2:37][CH2:38][CH3:39]
Reactant: CCCCN(CCCC)CCCN
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: CCCCN(CCCC)CCCNc1nc(-c2cc(C(=O)NC(C)C)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 96.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) were added N,N-dibutyl-1,3-propanediamine (0.041 mL, 0.182 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (24 mg, 96%). LC-MS m/z 622 (M+H)+; 1H-NMR (MeOD) δ 0.98 (t, 6H), 1.30 (m, 10H), 1.46 (m, 4H), 1.52 (m, 2H), 2.30 (s, 3H), 2.41 (m, 6H), 3.07 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.C(OCC)C>[Cl:12][CH2:11][C:4]1[CH:3]=[C:2]([F:13])[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=1
Reactant: [F-]
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)c1nc(F)cc(CCl)n1

Procedure:
A mixture of 0.8 g (0.0039 mol) of 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61), 0.51 g (0.0089 mol) of anhydrous potassium fluoride and 0.14 g (0.0004 mol) of 18-crown-6 in 7 ml of acetonitrile is heated at reflux temperature for 48 hours. The mixture is then taken up in diethyl ether and the solution is washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and freed from solvent under reduced pressure. The 4-chloromethyl-6-fluoro-2-isopropyl-pyrimidine is obtained in the form of a yellow oil, 1H-NMR (CDCl3): 1.32 (d, CH(CH3)2), 3.18 (m, CH(CH3)2), 4.62 (s, CH2Cl), 6.99 (d, CH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)(=[O:10])[CH3:9].C(OC(C)C)(C)C>C(O)=O>[CH3:16][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:8](=[O:10])[CH3:9])=[C:19]([CH2:1][N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:18]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: CC(=O)Nc1ccc(C)cc1CN1CCNCC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of formic acid (3.77 mL) at −10° C. was treated with 1-methylpiperazine (11.10 mL) dropwise whilst maintaining the temperature at −10° C. The reaction mixture was then allowed to warm to room temperature and treated with 4-acetamidobenzaldehyde (4.08 g). After stirring at 130° C. for 15 minutes the temperature was increased to 155° C. and stirring continued for 2.5 hours. The reaction mixture was allowed to cool to room temperature and treated with diisopropyl ether (50 mL). The insoluble material was washed with diethyl ether to give the title compound (3.98 g) as buff crystalline solid, m.p. 106–108° C. MS: 248 [MH]+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][NH2:11])([CH3:5])([CH3:4])[CH3:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][C@@H:20]([CH2:24][NH:25][C:26](=O)[O:27]C2C=CC([N+]([O-])=O)=CC=2)[CH2:19]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][C@@H:20]([CH2:24][NH:25][C:26]([NH:11][CH2:10][CH2:9][CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:12])=[O:27])[CH2:19]1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
4-Aminobutyric acid tert-butyl ester hydrochloride (0.235 g) was added to a stirred solution of Intermediate 13 (0.440 g) and N,N-diisopropylethylamine (0.42 ml) in dry dichloromethane (20 ml) under nitrogen, and the mixture was stirred at 22° C. for 18 h. The mixture was treated with saturated aqueous potassium carbonate (20 ml) and stirred for 5 min. The layers were separated and the organic layer applied to a silica gel cartridge (10 g Varian Bond Elut). Elution with dichloromethane, ether, ethyl acetate, and acetone gave the crude product (0.357 g). Further purification by chromatography on silica gel (10 g Varian Bond Elut cartridge), eluting with dichloromethane (1 column volume), ether (4 column volumes) and ethyl acetate (8 column volumes) gave the title compound as a gum (0.345 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](O)=[O:20]>CCOCC.C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:19](=[O:20])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc(C(=O)c2cccc(Cl)c2)c1
Temperature: -20 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
0.2 mol of butyl-lithium (a suspension in ether, containing 1.8 mol/liter) is placed in a 500 cm3 flask; it is cooled to -20° C. and 37.4 g (0.2 mol) of meta-bromoanisole diluted with 50 cm3 of anhydrous ether are added dropwise; when the addition has ended, the mixture is stirred for 10 to 15 minutes at the same temperature and 15.7 g (0.1 mol) of meta-chlorobenzoic acid dissolved in the minimum amount of THF are added dropwise; the temperature is allowed to return to ambient temperature and the reaction mixture is stirred for 2 hours under these conditions; it is then poured onto water, the ether is decanted and the aqueous phase is extracted with ether; the combined ether phases are washed with sodium bicarbonate and then with water, dried, decolorised and concentrated in vacuo. 26 g of a solid melting at 52° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[CH:3]([CH:28](C(OCC)=O)[C:29]([O:31]CC)=[O:30])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=4)[S:20][C:13]=23)=[C:7]([F:27])[CH:6]=1.[OH-].[Na+]>O.C(O)C>[F:40][C:2]([F:1])([F:39])[CH:3]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=4)[S:20][C:13]=23)=[C:7]([F:27])[CH:6]=1)[CH2:28][C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)C(C(=O)OCC)C(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(CC(=O)O)C(F)(F)F)cc4F)c3s2)c1
Yield: 36.9 %

Procedure:
A solution of 319 (490 mg, 0.84 mmol) and sodium hydroxide (338 mg, 8.44 mmol) in water (0.7 mL) and ethanol (3.4 mL) was stirred at room temperature for 48 h. The solvents were removed under reduced pressure and the residue was dissolved in water (20 mL). The solution was neutralized to pH 4 with a 3N HCl solution and the solid thus formed was filtered off, rinsed with water and dried. The solid was suspended in dry toluene (20 mL), heated to reflux for 1 h under continuous stirring, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent MeOH-dichloromethane, gradient 10:90 to 50:50) and the resulting solid was triturated in a mixture of dichloromethane, ethyl acetate and hexane, isolated by filtration, and dried under high vacuum to afford title compound 320 (150 mg, 0.31 mmol, 37% yield). LRMS (M+1) 480.9 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:24]1([CH2:30]N)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC1CCCCC1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(CC2CCCCC2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and cyclohexylmethanamine. MS (M−H, 416.1); NMR (400 MHz, DMSO-d6): δ, ppm: 0.63 (m, 2H), 0.87 (m, 3H), 0.94 (m, 1H), 1.25-1.52 (m, 5H), 1.70 (m, 2H), 2.86 (m, 2H), 3.70 (s, 3H), 4.22 (s, 2H), 6.84 (m, 2H), 7.16 (m, 2H), 7.91 (m, 2H), 7.62 (m, 2H), 8.09 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[C:12]3=[O:22])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:23][C:24]1[CH:29]=[N:28][C:27](Cl)=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:15][CH2:14][N:13]([CH:16]4[CH2:17][CH2:18][N:19]([C:27]5[CH:26]=[N:25][C:24]([Cl:23])=[CH:29][N:28]=5)[CH2:20][CH2:21]4)[C:12]3=[O:22])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1[C@@H](Oc2ccc3[nH]ncc3c2)CCN1C1CCNCC1
Reactant: Clc1cnc(Cl)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1[C@@H](Oc2ccc3[nH]ncc3c2)CCN1C1CCN(c2cnc(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
A flask was charged with (S)-3-(1H-indazol-5-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one (0.120 g, 0.400 mmol), 2,5-dichloropyrazine (0.0655 g, 0.439 mmol), DIEA (d 0.742) (0.0696 mL, 0.400 mmol), and DMF (3 mL). The reaction was stirred at 100° C. overnight. The organic solvents were removed under reduced pressure. The residue was purified using preparative TLC with 10% methanol in ethyl acetate to provide (S)-3-(1H-indazol-5-yloxy)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)pyrrolidin-2-one (0.0047 g, 0.0114 mmol, 2.85% yield). Mass spectrum (apci) m/z=413.2 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.O[CH2:20]C1C=C2C(=CC=1)C=C(C(C)C(O)=O)C=C2.[H-].[Na+].CI.Cl>C1C=CC=CC=1>[CH3:20][O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)C(C)c1ccc2cc(CO)ccc2c1
Reactant: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccccc1
Product: COCc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 2 h

Procedure:
To a mixture of 24.4 g. of methyl 6-hydroxymethyl-2-naphthyl-α -methylacetate (prepared from 6-hydroxymethyl-2-naphthyl-α -methylacetic acid by esterifying the latter by means of the procedure described in Part A of this example) and 500 ml. of benzene are added 2.4 g. of sodium hydride. The resulting mixture is stirred for two hours; then 12.2 g. of methyliodide are added. The resulting mixture is next neutralized by the addition of aqueous 1N hydrochloric acid after it has been allowed to stand for one hour; the mixture is then washed with water, dried over sodium sulfate, and evaporated to give methyl 6-methoxymethyl-2-naphthyl-α-methylacetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)[C:9]=1[CH:10]1[CH2:12][CH2:11]1)=O.[NH2:23][C:24]([NH2:26])=[NH:25]>>[CH:10]1([C:9]2[N:8]([C:13]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[N:7]=[CH:6][C:5]=2[C:3]([NH:25][C:24]([NH2:26])=[NH:23])=[O:2])[CH2:11][CH2:12]1
Reactant: COC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Reactant: N=C(N)N
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
coupling said 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid methyl ester with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[N:12]1([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:15][CH:14]([OH:16])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(O)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-hydroxy-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.69 g, 3.05 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 30 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give [1,3′]Biazetidinyl-3-ol as a colourless oil (0.225 g, 58%). LCMS (Method A): RT=0.29 min, [M+H]+ 288.9
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[N:22][C:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:20]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[N:23]=[N:22][C:21]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[C:20]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:34][CH:35]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCCCC2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCCCC3)nn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a stirred solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.40 mmol, 0.08 g) in THF (0.45 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.54 mmol, 0.022 g) and continued stirring for 10 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.27 mmol, 0.10 g) in THF (0.45 mL). After completion of addition, the reaction mixture was warmed to 65° C. and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×2 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 4 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 81%). To a solution of 4-[6-cyclohexyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.22 mmol, 0.12 g) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction was stirred for 30 min. The solvents were removed under reduced pressure and the residue was triturated with anhydrous ethyl ether (50 mL) and filtered to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.095 g).