Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH3:26][NH:27][CH3:28].CN1CCCC1=O.Cl>[Cl-].[Na+].O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][N:27]([CH3:28])[CH3:26])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Reactant: CNC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: CN(C)C[C@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (133 mg), dimethylamine (40% solution in water, 3 mL) and 1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in a sealed tube for 22 hours, cooled and poured into brine (50 mL), extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by Waters' MCX resin and then by reverse phase HPLC (gradient 25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid on Waters' Xterra™ column). The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the titled compound as a solid (41 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH2:30][CH:31]=C)[CH:24]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:33])[C:12]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:7][CH2:6]1)[CH:2]=C.[BH4-].[Na+]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[C:41]([O:40][C@@H:34]([C:12]1[C:13]([CH3:33])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:45])([O:4][CH2:1][CH2:2][CH2:31][CH2:30][CH2:29][C:25]2[CH:24]=[C:23]([CH2:22][O:21][CH2:20]3)[CH:28]=[CH:27][CH:26]=2)[CH2:10][CH2:9]1)[C:35]([O:37][CH2:38][CH3:39])=[O:36])([CH3:43])([CH3:42])[CH3:44]
Reactant: C=CCCc1cccc(COCc2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N4CCC(C)(OCC=C)CC4)n3n2)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1cccc(c1)COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((3-(but-3-en-1-yl)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.081 mmol) and Grubbs II catalyst (6.86 mg, 8.08 μmol) in DCM (50 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (3 mL). NaBH4 (15.28 mg, 0.404 mmol) was added and the reaction mixture was stirred at rt for 1 h. It was then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was then purified by biotage, eluting with 25% EtOAc/hexane to isolate ethyl (2S)-2-(tert-butoxy)-2-{4,24-dimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.113,17.02,7]triaconta-2,4,6(30),8,13(29),14,16-heptaen-3-yl}acetate (20 mg, 0.034 mmol, 41.8% yield) as a white solid. LCMS (M+1)=593.4. 1H NMR (400 MHz, CDCl3) δ 7.36-7.32 (m, 2H), 7.23-7.16 (m, 2H), 6.61 (s, 1H), 5.93 (s, 1H), 4.66 (s, 2H), 4.61-4.52 (m, 2H), 4.34 (td, J=12.3, 2.2 Hz, 1H), 4.27-4.16 (m, 2H), 3.85 (td, J=12.0, 2.2 Hz, 1H), 3.42-3.36 (m, 2H), 3.17 (d, J=11.7 Hz, 1H), 2.81 (dt, J=13.1, 6.3 Hz, 2H), 2.65-2.60 (m, 4H), 2.00 (dd, J=13.7, 2.2 Hz, 1H), 1.89 (dd, J=13.6, 2.1 Hz, 1H), 1.85-1.70 (m, 4H), 1.61-1.43 (m, 4H), 1.26-1.21 (m, 15H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[N:22]=[C:21]2[C:17](=[N:18][CH:19]=[N:20]2)[C:16](=[O:23])[N:15]=1)[CH2:2][CH3:3].[OH-].[Na+].C(O)(=O)C>O.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:14]2[N:22]=[C:21]3[C:17](=[N:18][CH:19]=[N:20]3)[C:16](=[O:23])[N:15]=2)[CH:7]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1C1=NC(=O)C2=NC=NC2=N1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CCCOc1ccc(N)cc1C1=NC(=O)C2=NC=NC2=N1

Procedure:
A solution of the crude product of Example 42 (1.5 g) in water (50 ml) containing 2 Normal sodium hydroxide (2.3 ml) and 10% palladium on charcoal (0.15 g) was shaken under hydrogen (50 psi) until the uptake was complete. Neutralisation of the filtered solution with acetic acid gave a fine precipitate of 2-(5-amino-2-propoxyphenyl)-purin-6-one. This mixture was warmed with 2 Normal hydrochloric acid (2.5 ml) and the solution was treated with acetic anhydride (0.55 ml) and sodium acetate trihydrate (0.8 g). The mixture was warmed for 10 minutes then cooled and filtered to give a crude product (1.02 g) which was recrystallised from aqueous dimethylformamide twice to give the title compound, 0.49 g, m.p. 320-323° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.[OH-].[K+].Cl[CH2:21][C:22]1[NH:23][CH2:24][CH2:25][CH2:26][N:27]=1.Cl>CS(C)=O>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:21][C:22]3[NH:27][CH2:26][CH2:25][CH2:24][N:23]=3)[C:6]=2[N:14]=1
Reactant: ClCC1=NCCCN1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: NC(=O)c1cc2c3ccccc3n(CC3=NCCCN3)c2nc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a stirred solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 100 mg, 0.44 mmol) in dimethyl sulfoxide (1 mL) was added powdered potassium hydroxide (370 mg, 6.6 mmol), and the resulting mixture stirred at room temperature for 10 min. 2-(Chloromethyl)-1,4,5,6-tetrahydropyrimidine.HCl (Stillings, M. R., J. Med. Chem. 1986, 29, 2280-2284; 220 mg, 1.3 mmol) in dimethyl sulfoxide (1 mL) was added dropwise to the mixture over 0.5 h at 5-10° C. Upon completion of addition, the reaction was allowed to stir overnight at room temperature. The crude reaction mixture was concentrated under reduced pressure and purified by HPLC (Phenomenex Luna 15 μm C18, aqueous HCOOH/CH3CN) to yield 2-amino-9-(1,4,5,6-tetrahydropyrimidin-2-ylmethyl)-9H-pyrido[2,3-b]indole-3-carboxamide (32, 14 mg, 10%). NH4OAc standard conditions. DAD Retention time =4.42 min. M+H=323. 1H NMR (300 MHz, MeOD): δ 8.73 (s, 1H), 8.49 (s, 1H), 7.94 (d, J=6.9 Hz, 1H), 7.42-7.40 (m, 2H), 7.33-7.27 (m, 1H), 5.29 (s, 2H), 3.45 (t, J=5.7 Hz, 4H), 2.04 (t, J=5.7 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:7]=C([CH:11]=[CH:12][CH:13]=1)C#N)=[O:5].Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[OH:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:7]=[C:22]([CH:11]=[CH:12][CH:13]=1)[C:21]([OH:24])=[O:23])=[O:5]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)c2cccc(C#N)c2)c(O)c1
Agent: Cl
Product: COc1ccc(C(=O)c2cccc(C(=O)O)c2)c(O)c1

Procedure:
A solution of, 3-(2-hydroxy-4-methoxybenzoyl)benzonitrile (from the synthesis of Example 26; 2.75 g) in a mixture of concentrated hydrochloric acid (30 g) and acetic acid (30 g) is heated under reflux for 4 hours. The precipitate which forms is collected by filtration and recrystallized from ethanol to yield 3-(2-hydroxy-4-methoxybenzoyl)benzoic acid (1.5 g), m.p. 229°-236° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2s1
Yield: 64 %

Procedure:
Prepared from VII and 3-chloro-4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 64%; yellow solid; mp 252° C.; IR (KBr) νmax/cm−1 3456, 3015, 2970, 2946, 2229, 1642, 1441, 1153, 1129, 1051, 968, 903, 817, 774, 695; 19F NMR (282 MHz, DMSO-d6) δ −123.8; 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, 1H, J=9.0 Hz), 8.30 (s, 1H), 7.62 (m, 2H), 7.34 (m, 2H); HRMS calcd for C16H7N5SClF (M+H+): 356.0156, found 356.0167.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7].N1C=CN=C1.[CH2:19]([Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])Cl)[CH3:20]>CCCCCC>[C:6]([C:8]1([O:13][Si:21]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:19][CH3:20])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[CH:7]
Reactant: C#CC1(O)CCCC1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CC1(O[Si](CC)(CC)CC)CCCC1
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
To a dimethylformamide solution (49.5 ml) of 1-ethynyl-1-hydroxycyclopentane (5.45 g, 49.5 mmol) were added imidazole (6.74 g, 99.0 mmol) and triethylchlorosilane (9.97 ml, 59.4 mmol) at room temperature, followed by stirring for 30 minutes. The reaction solution was added to a mixture of n-hexane and a saturated aqueous sodium bicarbonate solution, and the organic layer was separated. The aqueous layer was extracted with hexane, and the organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. After filtration, the filtrate was evaporated under reduced pressure to give the title compound (9.26 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28]CC3C=CC([N+]([O-])=O)=CC=3)=[O:27])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].I[CH2:42][C:43]([NH2:45])=[O:44].C(OCC)(=O)C>CC(C)=O>[C:43]([CH2:42][N+:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:19][C:16]1[N:17]=[CH:18][N:13]2[CH:12]=[C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:39](=[O:40])[N:6]4[C:7]=3[C:26]([O-:28])=[O:27])[S:15][C:14]=12)(=[O:44])[NH2:45]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(Sc5ccccn5)c4s3)[C@H](C)[C@H]12
Reactant: NC(=O)CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(Sc5cccc[n+]5CC(N)=O)c4s3)[C@H](C)[C@H]12
Temperature: 40 °C
Reaction time: 96 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (42.2 mg) was dissolved in 2 ml of acetone. 2-Iodoacetamide (140 mg) was added to the solution. The mixture was stirred at 40° C. for 4 days. Ethyl acetate (4 ml) was added to the reaction solution, and the resultant precipitate was collected, and was reacted in the same manner as in Example 1c). The reaction product was purified by column chromatography on Cosmosil 40C18-PREP (a 10 to 25% aqueous methanol solution). In this case, the first eluted fraction in two major products was collected to prepare 1.44 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([Cl:13])=[CH:4][N:3]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][C:24](O)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][C:24]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]3[C:5]([Cl:13])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[CH3:15]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: OCCCNc1nc(Cl)ncc1Cl
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ncc3Cl)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.5 %

Procedure:
To a solution of 3-[(2-chloro-5-chloro-4-pyrimidinyl)amino]-1-propanol (Example 440, 1.08 g, 4.90 mmol) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 539 mg, 2.45 mmol) in THF (40 mL) were added PPh3 (1.29 g, 4.90 mmol) and ADDP (1.26 g, 4.90 mmol). The reaction mixture was vigorously stirred at rt for 72 h, after which additional amounts of PPh3 (1.29 g, 4.90 mmol) and ADDP (1.26 g, 4.90 mmol) were added. After stirring for an additional 24 h, the reaction mixture was diluted with hexanes, filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was then purified by silica gel chromatography (1:1 hexanes/EtOAc) to give the product (920 mg, 89%). 1H NMR (400 MHz, CDCl3): δ 1.29 (t, 3H), 1.71-1.82 (m, 1H), 2.15 (qt, 2H), 2.35-2.47 (m, 2H), 2.72 (dd, 1H), 2.79-2.98 (m, 2H), 3.48-3.58 (m, 1H), 3.74 (q, 2H), 4.12 (t, 2H), 4.18 (q, 2H), 6.22-6.31 (b, 1H), 6.73 (dd, 1H), 6.79 (d, 1H), 7.08 (d, 1H), 7.25 (s, 1H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([CH3:34])=[C:11]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:7]=1)(=O)C.[CH3:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:30]([O:29][C@@H:23]([C:11]1[C:12]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:13]2[C:8](=[CH:9][C:10]=1[CH3:34])[N:7]=[C:6]([C:5](=[O:4])[N:36]([CH3:35])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH:15]=[CH:14]2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:31])([CH3:33])[CH3:32]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(COC(C)=O)ccc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)N(C)c3ccccc3)ccc2c1-c1ccc(Cl)cc1

Procedure:
(S)-Ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(methyl(phenyl)carbamoyl) quinolin-6-yl)acetate was prepared following the procedure used to prepare compound (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(dimethylcarbamoyl)-7-methylquinolin-6-yl)acetate of Example 16, except that N-methylaniline was used instead of dimethylamine HCl salt. LCMS-ESI+ (m/z): 545.2, 547.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([C:13]3[C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=4[O:10][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:32])=[CH:34][CH:35]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Agent: Cl
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield from 2-(4-methoxyphenyl)benzofuran (Part A) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride by essentially following the procedure detailed in Example 1, Part C.
Reaction SMILES: BrC1C2C(=CC=C(C(=O)NCC3CCCC3)C=2)N(CC(=O)N)N=1.BrCC1C=CC(C(OC)=O)=CC=1OC.[CH:38]1([CH2:43][NH:44][C:45]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH2:56][C:57](=[O:59])[NH2:58])[N:51]=[C:50]3[CH2:60][C:61]2[CH:70]=[CH:69][C:64]([C:65]([O:67]C)=[O:66])=[CH:63][C:62]=2[O:71][CH3:72])=[O:46])[CH2:42][CH2:41][CH2:40][CH2:39]1>[Zn].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].Cl[Ni](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:38]1([CH2:43][NH:44][C:45]([C:47]2[CH:48]=[C:49]3[C:53](=[CH:54][CH:55]=2)[N:52]([CH2:56][C:57](=[O:59])[NH2:58])[N:51]=[C:50]3[CH2:60][C:61]2[CH:70]=[CH:69][C:64]([C:65]([OH:67])=[O:66])=[CH:63][C:62]=2[O:71][CH3:72])=[O:46])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: COC(=O)c1ccc(Cc2nn(CC(N)=O)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Product: COc1cc(C(=O)O)ccc1Cc1nn(CC(N)=O)c2ccc(C(=O)NCC3CCCC3)cc12

Procedure:
The cross coupling process may be carried out, for example, using a stoichiometric amount of activated zinc dust and a catalytic quantity of a transition metal catalyst, such as, for example, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) or dichlorobis(triphenylphosphine)nickel(II) to couple, for example, 3-bromo-5-(N-cyclopentylmethylcarbamoyl)-1-(carbamoylmethyl)indazole with, for example, methyl 4-bromomethyl-3-methoxybenzoate to afford methyl 4-[5-(N-cyclopentylmethylcarbamoyl)-1-(carbamoylmethyl)indazol-3-ylmethyl]-3-methoxybenzoate; followed by decomposition of the ester to afford 4-[5-(N-cyclopentylmethylcarbamoyl)-1-(carbamoylmethyl)indazol-3-ylmethyl]-3-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Sn](C)(C)C)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][N:23]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:22]2[N:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][N:23]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc(Cl)nc1C
Reactant: C[Sn](C)(C)c1nn(Cc2ccccc2)c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cc1cnc(-c2nn(Cc3ccccc3)c3ccccc23)nc1C
Temperature: 25 °C

Procedure:
640 mg of 1-benzyl-3-trimethylstannylindazole (1.72 mmol), 212 mg of 2-chloro-4,5-dimethylpyrimidine* (1.49 mmol) and 72 mg (0.10 mmol) of Pd(PPh3)2Cl2 (5.8 mol %) in 20 ml of toluene were heated under reflux overnight in an argon atmosphere. The mixture was cooled to room temperature, saturated ammonium chloride solution was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification was carried out by chromatography over silica gel using cyclohexane/ethyl acetate as the eluent (gradient from 10:1 to 1:1).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]([O:12][CH:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].Cl.[CH3:30][NH:31][CH3:32]>CC(C)=O.C1(C)C=CC=CC=1>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]([O:12][CH:13]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:31]([CH3:32])[CH3:30])=[O:19])=[CH:21][CH:22]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2]
Reactant: CNC
Reactant: CC(C)C[C@H](OC(c1ccccc1)c1ccc(C(=O)O)cc1)C(=O)NCC#N
Agent: Cl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(C(=O)N(C)C)cc1)C(=O)NCC#N

Procedure:
Using the same coupling procedure as described for example 47, 4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoic acid (51 mg, 0.134 mmol) was reacted with dimethylamine hydrochloride (11 mg, 0.134 mmol, 1 eg) to give the title compound as an oil after chromatography with 25% acetone/toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([N:13]=[C:14](SC)SC)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([NH:13][C:14]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: COc1nc(C)nc2sc(N=C(SC)SC)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C)nc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc12
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of dimethyl 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (56 mg, 0.19 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (51 mg, 0.22 mmol) and cesium carbonate (175 mg, 0.54 mmol) in DMF (0.5 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (34 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (br. s., 1 H) 4.14 (s, 3 H) 4.03 (d, J=9.54 Hz, 1 H) 3.68 (d, J=9.54 Hz, 1 H) 3.39 (dd, J=14.93, 1.63 Hz, 1 H) 2.74-3.07 (m, 5 H) 2.68 (s, 3 H) 2.04-2.28 (m, 2 H) 1.70-1.86 (m, 1 H) 1.44-1.67 (m, 2 H). MS (LC/MS) R.T.=1.10; [M+H]+=361.32.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[C:10]=1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31]>CO.C(OCC)(=O)C.[Pd]>[CH3:33][O:32][C:30](=[O:31])[CH2:29][CH2:28][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:34]
Reactant: COC(=O)C=Cc1c(C#CCCCCOC2CCCCO2)cccc1OCCCCC(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCCCOc1cccc(CCCCCCOC2CCCCO2)c1CCC(=O)OC

Procedure:
A 0.9 g (1.9 mmol) sample of rac-5-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexyn-1-yl]phenoxy]pentanoic acid methyl ester was hydrogenated in 60 mL of 1:1 methanol-ethyl acetate, over 70 mg of 10% palladium on carbon, at room temperature and 1 atmosphere. rac-2-(5-Methoxy-5-oxopentyloxy)-6-[6-[(tetrahydro-2-H-pyran-2-yl)oxy]hexyl]benzenepropanoic acid methyl ester, an oil, was isolated by filtration of the catalyst and concentration of the filtrate, in quantitative yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([O:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:66])(=O)=O)CCCCCCCCCCCCCCC>>[I:66][CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([NH:34][C:35]([O:37][CH3:38])=[O:36])[CH2:11][O:12][C:13](=[O:33])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(=O)OC

Procedure:
3-(3-Chloropropylsulfonylamino)-2-methoxycarbonylamino-1-octadecylcarbamoyloxypropane IIIe1 is allowed to react and worked up by the same procedure as described in (5). m.p. 97° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[N:7]3[CH2:14][CH2:15][CH2:16][N:17]=[C:6]3[C:5]=2[CH:4]=1.[CH2:20](Br)[CH:21]=[CH2:22]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:22][CH:21]=[CH2:20])[C:8](=[O:13])[N:7]3[CH2:14][CH2:15][CH2:16][N:17]=[C:6]3[C:5]=2[CH:4]=1
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C2=NCCCN12
Reactant: C=CCBr
Product: C=CCN1C(=O)N2CCCN=C2c2cc(C(F)(F)F)ccc21

Procedure:
Preparation analogously to Example 29 from 10-trifluoromethyl-6-oxo-2,3,4,5,6,7-hexahydropyrimido-[1,2-c]-quinazoline and allyl bromide.