Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:5]=2[N:6]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI.O>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(C(=O)O)ccc2s1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2sc(C)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of commercially available 2-methylbenzo[d]thiazole-5-carboxylic acid (1.500 g; 7.76 mmol) in anh. DMF (35 ml) was treated with Cs2CO3 (3.161 g; 9.70 mmol), and the heterogeneous mixture was further stirred at rt, under nitrogen, for 15 min. The mixture was then cooled to 0° C., and CH3I (1.652 g; 11.64 mmol) was added dropwise. The resulting mixture was further stirred at 0° C. for 10 min., and then at rt for 16 h. Water and AcOEt were added to the reaction mixture. The separated organic layer was further washed with water and brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 2-methylbenzo[d]thiazole-5-carboxylate as a brown solid. LC-MS (conditions A): tR=0.67 min.; [M+H]+: 208.16 g/mol.
Reaction SMILES: Cl[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[NH2:13][C:14]1[C:29]([Cl:30])=[CH:28][C:17]([C:18]([O:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:19])=[C:16]([O:31][CH3:32])[CH:15]=1.C(N(CC)CC)C>CN(C=O)C>[NH2:13][C:14]1[C:29]([Cl:30])=[CH:28][C:17]([C:18]([O:20][CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:4][CH2:3][CH2:2][O:5][C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[CH2:26][CH2:27]2)=[O:19])=[C:16]([O:31][CH3:32])[CH:15]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)OCC1CCNCC1
Reactant: CCC(Cl)Oc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)OCC1CCN(CCCOc2ccc(F)cc2)CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 25.8 %

Procedure:
A mixture of 1-chloro-(4-fluorophenoxy)propane (2.3 g), intermediate 11 (3 g) and N,N-diethylethanamine (2.8 ml) in DMF (50 ml) was stirred for 48 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was partitioned between DCM and water. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN (0° C.). The precipitate was filtered off and dried (vacuum; 50° C.), yielding 1.17 g (26%) [1-[3-(4-fluorophenoxy)propyl]-4-piperidinyl]methyl 4-amino-5-chloro-2-methoxybenzoate (compound 1, mp. 140.0° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>ClCCl.[OH-].[Na+]>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Reaction time: 12 h

Procedure:
3′-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed in dichloromethane with potassium carbonate (121 mg) and isobutyryl chloride (94 mg). After 12 hours, the mixture was diluted with sodium hydroxide solution and washed with diethyl ether. The aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 283.33 (C17H17NO3); MS (ESI): 284 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=O)[CH2:26][C:25]2([CH3:33])[CH3:32].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:27]3[C:28]4[C:24](=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=4)[C:25]([CH3:33])([CH3:32])[CH2:26]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC1(C)CC(=O)c2ccc(Cl)cc21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC(C)(C)c4cc(Cl)ccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 5-chloro-3,3-dimethyl-indan-1-one (prepared according to Claiborne, C. F. et al., Int. patent application WO 2008/019124) using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=457.4 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.Cl>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (1.0 g, 3.89 mM), 3-methylbenzyl bromide (0.54 ml, 3.97 mM), and potassium carbonate (1.07 g, 7.78 mM) in 20 mL DMF was stirred at room temperature for 19 hours. The mixture was diluted with EtOAc and 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc. The combined EtOAc layers were extracted with 1N HCl, water, then brine. After drying (NaSO4), evaporation in vacuo afforded 1.41 g (100%) of 9-[(3-methylphenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ7.4-7.05 (m, 6H), 6.8 (m, 1H), 5.3 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.7-2.3 (m, 4H), 2.3 (s, 1H), 1.2 (d, J=7 Hz, 3H). MS (ES) m/e 362.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[Li].C([Li])CCC.O1C=CC=C1.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[Cl-].[NH4+]>CCOCC.CCCCCC>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[OH:23]
Reactant: [Li]c1ccco1
Reactant: OCCCCCCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccoc1
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(CCCCCl)c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 2-furyllithium [prepared from 0.53 moles of n-butyllithium and 39.5 g of furan by the procedure of J. Org. Chem., 27, 1216 (1962)] in 350 ml of ether and with 200 ml of hexane at -78° C. is added a solution of 57.9 g of 5-chloropentanol [Chem. Abstr., 59, 7579F (1963)] in 80 ml of ether during 25 minutes. The mixture is warmed to 0° C. during 20 minutes, stirred at 0° C. for 15 minutes, and treated with 140 ml of saturated ammonium chloride. The ether phase is washed with water and brine, dried over magnesium sulfate and potassium carbonate mixture, and concentrated to give a liquid, pmr spectrum (CDCl3): δ3.59 (triplet, CH2Cl) and 4.70 (triplet, CH2CHOH).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH2:54][C:55]1[CH:59]=[CH:58][N:57]([CH2:60][C:61]([CH3:64])([OH:63])[CH3:62])[N:56]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:54][C:55]2[CH:59]=[CH:58][N:57]([CH2:60][C:61]([OH:63])([CH3:62])[CH3:64])[N:56]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3)cc2=O)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.9 %

Procedure:
A solution of 3-cyclopentyl-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionic acid (Intermediate 19, 100.6 mg, 0.30 mmol) in methylene chloride (1.70 mL, 0.18M) at 25° C. was treated with N,N-diisopropylethylamine (160 μL, 0.91 mmol) followed by N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (110.6 mg, 0.36 mmol). The resulting solution was stirred at 25° C. for 2.5 h. After this time, the reaction was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1, 61.8 mg, 0.39 mmol). The resulting solution was stirred at 25° C. for 2 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were washed with water (3×100 mL), dried over sodium sulfate and concentrated in vacuo. Silica gel column chromatography (ISCO 40 g, 1/1-3/1 ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(6-oxo-4-phenoxy-6H-pyridazin-1-yl)-propionamide (23.6 mg, 16.5%) as a white solid; ES+-HRMS m/e calcd for C25H31N5O4 [M+H+] 466.2449, found 466.2450. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.00-1.76 (m, 9H), 1.91 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.46 (dd, J=3.9, J=11.2 Hz, 1H), 5.72 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 1H), 7.46-7.64 (m, 3H), 8.12 (d, J=2.7 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([N:12]3[CH2:15][C:14]([F:17])([F:16])[CH2:13]3)=[CH:10][N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:21][CH:22]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:23]([NH2:25])=[O:24].Cl>>[NH2:25][C:23](=[O:24])[CH:22]([NH:21][C:18]([C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:11]([N:12]2[CH2:13][C:14]([F:16])([F:17])[CH2:15]2)=[CH:10][N:9]=1)=[O:20])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)C(N)C(N)=O
Reactant: O=C(O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1
Agent: Cl
Product: CC(C)(C)C(NC(=O)c1cc(OCC2CC2)c(N2CC(F)(F)C2)cn1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-Cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (example 53e) and 2-Amino-3,3-dimethyl-butyramide; hydrochloride (CAN 113582-42-6) as starting materials and isolated (58 mg, 83%); MS (ESI, m/z): 397.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[N:24]=3)[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:29])[N:24]=3)[CH:18]=2)[S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CNCc2cccc(-c3ccnc(Cl)n3)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(CN(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1

Procedure:
Intermediate 55 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 495.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([OH:13])[CH2:9][N:10]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH:8]([OH:13])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)Cc1ccccc1
Yield: 102.7 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 6.0 g of 3-phenyl-2-hydroxypropylazide (prepared as described in Preparation 16), 2.6 g of lithium aluminum hydride and 300 ml of anhydrous tetrahydrofuran were used, to give 5.26 g of the title compound, melting at 64° C. to 66° C.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH2:2].[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.O>[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:3]/[CH:1]=[CH:2]/[C:13]1[C:12]([Cl:16])=[CH:11][N:10]=[C:9]([Cl:8])[N:14]=1)[CH2:5][CH2:6][CH3:7]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCO/C=C/c1nc(Cl)ncc1Cl
Temperature: 80 °C
Yield: 90.8 %

Procedure:
Degassed 1,4-dioxane (600 mL) was added to palladium(II) acetate (4.80 g, 21.37 mmol) under N2. n-Butyl vinyl ether (275 mL, 2.137 mol), 2,4,5-trichloropyrimidine (200 g, 1.069 mol) and DIPEA (194 mL, 1.122 mol) were then added. The mixture was heated to 80° C. for 22.5 h and then cooled to 30° C. Palladium acetate (2.40 g, 10.68 mmol), n-butyl vinyl ether (138 mL, 1.068 mol) and DIPEA (97 mL, 561 mmol) were then added. The mixture was then heated to 80° C. for 4 h and then allowed to cool to r.t. overnight. The mixture was then added to water (2 L), and then sat. brine (2 L) was added. The phases were separated and the aqueous solution was extracted with methyl-tert-butylether (2×1 L). The combined organic solutions were washed with water resulting in an emulsion which would not separate. Everything was filtered and the two phases were then separated. The organic solution was dried (MgSO4) and concentrated to give a brown oil (240 g). This material is was split into two batches and each purified by FCC, eluting with 0-100% heptane in CH2Cl2 to give the title compound (130 g, 49%) as a yellow oil; 1H NMR: 0.89-0.97 (3H, t), 1.33-1.45 (2H, m), 1.62-1.72 (2H, m), 4.13 (2H, t), 6.08 (1H, d), 8.06 (1H, d), 8.64 (1H, s); m/z: ES+ MH+ 247.41.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 1.0 M potassium tert-butoxide in tetrahydrofuran (30.7 mL, 0.0307 mol) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (5.20 mL, 0.0322 mol) in tetrahydrofuran (39.12 mL). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.0 g, 0.029 mol, Aldrich: Cat. #696315) in tetrahydrofuran (7.82 mL). The reaction was allowed to warm to room temperature and stirred overnight. After quenched with water, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated under reduced pressure. The crude mixture was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-70%) to give the desired product (5.40 g, 95%). LCMS (M+Na)+: m/z=217.1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[C:13]2[C:8](=[C:9]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(C1C=C2C(=CC=1)NC=C2)#CCCCCCC>>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CCCCCCC#Cc1cccc2c1CCN2C(=O)C(F)(F)F
Agent: CCCCCCC#Cc1ccc2[nH]ccc2c1
Product: CCCCCCCCc1cccc2c1CCN2C(=O)C(F)(F)F
Yield: 77 %

Procedure:
When the product of Step B was substituted for 5-(oct-1-ynyl)-1H-indole in Example 3, Step B, the identical process afforded the title compound in 77% yield, as colourless oil. 1H-NMR (CDCl3) 0.86 (m, 3H); 1.28 (m, 10H); 1.57 (m, 2H); 2.54 (tr, 2H, J=8 Hz); 3.17 (tr, 2H, J=8.3 Hz); 4.27 (tr, 2H, J=8 Hz); 6.97 (d, 1H, J=7.6 Hz); 7.2 (tr, 1H, J=7.9 Hz); 8.04 (d, 1H, J=8.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[CH2:20](I)[CH3:21]>>[CH2:20]([N:7]1[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)[CH3:21]
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: CCI
Product: CCn1nc(-c2ccc(OC)cc2)cc(C(=O)OC)c1=O
Yield: 79.4 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethyl iodide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 79.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[O:6][CH2:7][CH2:8][N:9]1[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:18].CCN(C(C)C)C(C)C.[S:33]1[C:37]2[CH:38]=[C:39]([S:42](Cl)(=[O:44])=[O:43])[CH:40]=[CH:41][C:36]=2[N:35]=[CH:34]1>C(Cl)Cl>[S:33]1[C:37]2[CH:38]=[C:39]([S:42]([N:17]3[CH:15]4[CH2:14][CH2:13][CH2:12][CH:11]3[C:10](=[O:18])[N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16]4)(=[O:43])=[O:44])[CH:40]=[CH:41][C:36]=2[N:35]=[CH:34]1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: COc1ccc(OCCN2CC3CCCC(N3)C2=O)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCN2CC3CCCC(C2=O)N3S(=O)(=O)c2ccc3ncsc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxyl)ethyl)-3,9-diazabicyclo[3.3.1]nonan-2-one (32 mg, 0.1 mmol) in 3 ml DCM was treated with DIPEA (15 mg, 0.12 mmol) and stirring for 30 min at room temperature followed by addition of 1,3-benzothiazole-6-sulfonyl chloride (28 mg, 0.12 mmol). The reaction was stirred overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-TLC in 10% MeOH in CHCl3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1[C:17]#[N:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH2:32]OS(C)(=O)=O)=[N:29][N:28]=2)=[C:23]([C:38]([F:41])([F:40])[F:39])[CH:22]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:17]#[N:18])=[C:10]2[C:15]([N:16]=1)=[CH:14][N:13]([CH2:32][C:30]1[S:31][C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][C:23]=3[C:38]([F:41])([F:39])[F:40])=[N:28][N:29]=1)[CH:12]=[N:11]2
Reactant: COc1ccc(-c2nnc(COS(C)(=O)=O)s2)c(C(F)(F)F)c1
Reactant: N#Cc1c(-c2ccccc2F)[nH]c2cncnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(Cn3cnc4c(C#N)c(-c5ccccc5F)nc-4c3)s2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 8.5 %

Procedure:
To a solution of 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile (29 mg) and methanesulfonic acid 5-(4-methoxy-2-trifluoromethylphenyl)-[1,3,4]thiadiazol-2-ylmethyl ester (49 mg) in DMF was added NaH (5 mg). The reaction was stirred for 14 h at rt. The reaction was quenched by slow addition of AcOH (glacial), filtered, and purified by HPLC (10-70% MeCN/H2O with 1% formic acid) then lyophilized to give 5.3 mg of the titled compound (8%). 1H NMR (DMSO-d6): 9.40 (s, 1 h), 9.18 (s, 1 h), 7.85 (t, 1 h), 7.73 (d, 1H), 7.56-7.64 (m, 1H), 7.35-7.47 (m, 4H), 6.30 (s, 2H), 3.93 (s, 3H). LC-MS calculated for C24H14F4N6OS 510.5, found 511.00 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=2)=[C:10](\[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH:11]=[CH2:12])=[CH:5][CH:4]=1.[OH-].[Na+].Cl.O>CCO.C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[C:9](/[C:19]2[CH:20]=[CH:21][C:22](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])=[CH:23][CH:24]=2)=[C:10](\[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH2:11][CH3:12])=[CH:7][CH:8]=1
Reactant: C=C/C(=C(\c1ccc(/C=C/C(=O)OCC)cc1)c1ccc(OC)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC/C(=C(\c1ccc(/C=C/C(=O)O)cc1)c1ccc(OC)cc1)c1ccccc1
Temperature: 25 °C
Yield: 106 %

Procedure:
Compound 5 (39.80 g, 96.5 mmol) was dissolved in EtOH (300 mL) and THF (300 mL). 1 M aqueous NaOH (250 mL, 250 mmol) was added and the solution refluxed for 2 h. The reaction was cooled to RT and then acidified to pH 2 with 6N aq. HCl. H2O (750 mL) and CH2Cl2 (500 mL) were added and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organics were dried (Na2SO4) and concentrated to provide the title compound, 6 (39.34 g, 100%), as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 0.95 (t, J=7.4 Hz, 3H), 2.48 (q, J=7.4 Hz, 2H), 3.69 (s, 3H), 6.46 (d, J=15.8 Hz, 1H), 6.56 (d, J=8.6 Hz, 2H), 6.77 (d, J=8.6 Hz, 2H), 7.10-7.12 (m, 3H), 7.13-7.19 (m, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.80 (d, J=15.8 Hz, 1H).
Reaction SMILES: S(O[CH:12]1[CH2:30][CH2:29][N:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]2[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH3:31][NH:32][CH3:33].O>CS(C)=O>[CH3:31][N:32]([CH3:33])[CH:12]1[CH2:30][CH2:29][N:15]2[C:16]3[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=3[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH:14]2[CH2:13]1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OC2CCN3c4ccccc4Cc4ccccc4C3C2)cc1
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g of 2-tosyloxy-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a] -dibenzo[ c,f]-azepine (eg.) are dissolved in 50 ml of dimethylsulphoxide. After that 15 ml of dimethylamine are added to the solution. This solution is now heated in a sealed ampoule on a vapour-bath for 2 hours. After cooling the solution, it is poured into 300 ml of water after which the mixture is extracted with 3×200 ml of ether. The ether layers are washed and then dried, whereupon the solvent is evaporated and the residue is recrystallized. Yield: 1.3 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:22](=[O:40])(=[O:39])[NH:23][C:24]2[CH:25]=[CH:26][C:27]3[C@H:28]4[CH2:38][C@H:29]4[CH2:30][O:31][C:32]=3[C:33]=2[C:34]([O:36][CH3:37])=[O:35])=[C:6]([CH:21]=1)[CH2:7][O:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1.ClS(C1C=CC(F)=CC=1CO[C@@H]1CCN(C(OC(C)(C)C)=O)C1)(=O)=O.NC1C(C(OC)=O)=C2C([C@H]3C[C@H]3CO2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:22](=[O:39])(=[O:40])[NH:23][C:24]2[CH:25]=[CH:26][C:27]3[C@H:28]4[CH2:38][C@H:29]4[CH2:30][O:31][C:32]=3[C:33]=2[C:34]([O:36][CH3:37])=[O:35])=[C:6]([CH:21]=1)[CH2:7][O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CO[C@H]2CCN(C(=O)OC(C)(C)C)C2)ccc2c1OC[C@@H]1C[C@H]21
Agent: CC(C)(C)OC(=O)N1CC[C@@H](OCc2cc(F)ccc2S(=O)(=O)Cl)C1
Agent: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CO[C@@H]2CCN(C(=O)OC(C)(C)C)C2)ccc2c1OC[C@@H]1C[C@H]21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 214, starting from tert-butyl (R)-3-(2-chlorosulfonyl-5-fluorobenzyloxy)pyrrolidine-1-carboxylate (Intermediate 219) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A).