Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:22]=1[Cl:28])=[O:17])C>>[Cl:28][C:22]1[CH:23]=[C:24]([O:27][CH2:2][C:3]2[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:25]=[CH:26][C:21]=1[CH:19]1[CH2:20][CH:18]1[C:16]([OH:17])=[O:15]
Reactant: CCOC(=O)C1CC1c1ccc(O)cc1Cl
Reactant: CC(C)Sc1ncccc1CCl
Product: CC(C)Sc1ncccc1COc1ccc(C2CC2C(=O)O)c(Cl)c1
Yield: 54.2 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.040 g, 0.20 mmol) obtained in Step C of Preparation Example 1 and 2-(2-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.047 g, 0.20 mmol) obtained in Step E of Preparation Example 45 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041 g, 55%).
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[OH:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]>>[Cl:5][S:1]([C:14]1[CH:15]=[CH:16][C:7]([OH:6])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)c1ccccc1O
Product: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sulfurochloridic acid (38.3 g, 329 mmol) at 0° C. was added to methyl 2-hydroxybenzoate (10 g, 65.7 mmol) in small portions and the mixture was then stirred at 0° C. for 1 h. The mixture was added dropwise to 10 ml ice-water with stirring and stirring continued for an additional 0.5 h. The ensuing white crystals were collected by filtration, washed three times with water, and then dried to yield the title compound. 12 g.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([F:10])([F:9])[CH:4]([OH:8])[CH2:5][CH2:6]I.[N-:13]=[N+:14]=[N-:15].[Na+].O>CS(C)=O>[N:13]([CH2:6][CH2:5][CH:4]([OH:8])[C:3]([F:10])([F:9])[C:2]([F:12])([F:11])[F:1])=[N+:14]=[N-:15]
Reactant: OC(CCI)C(F)(F)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCC(O)C(F)(F)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
A solution of 1,1,1,2,2-pentafluoro-5-iodo-3-pentanol (1.99 g, 7.48 mmol) in dimethylsulfoxide (20 ml) was treated with sodium azide (585 mg, 8.98 mmol) and the reaction was heated to 50° C. After stirring overnight, the reaction was cooled to room temperature. It was then added to water (30 ml) and extracted with diethyl ether (3×30 ml). The combined organics were washed with brine (40 ml) and dried over anhydrous sodium sulphate. Removal of the solvents yielded an orange liquid. Purification by silica gel chromatography using 1:1 hexanes/ethyl acetate gave the title compound as an orange liquid (1.7 g, 100%).
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[CH2:25]([Sn](CCCC)(CCCC)C#C)[CH2:26]CC.C(OCC)(=O)C>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([C:25]#[CH:26])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1Oc1ccccc1)CC[C@H](C)N2C(=O)C1CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.030 g, 0.08 mmol), tributyl(ethynyl)stannane (0.030 g, 0.09 mmol), and tetrakis(triphenylphosphine)palladium (O) (0.037 g, 0.03 mmol) in N,N-dimethylformamide (1.5 mL) stirred overnight at 120° C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (15 mL), washed with water (2×5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:5, ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters III): Column, Xbridge RP C18, 19×150 mm, 5 um; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded (S)-cyclopropyl(6-ethynyl-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.004 g, 16%) as a brown semi-solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.65-0.85 (m, 1H), 0.87-1.04 (m, 2H), 1.05-1.25 (m, 4H), 1.38-1.52 (m, 1H), 1.85-2.02 (m, 1H), 2.11-2.47 (m, 2H), 2.62-2.85 (m, 1H), 3.47 (m, 1H), 4.75-4.82 (m, 1H), 6.79 (d, J=8.10 Hz, 2H), 6.95-7.05 (m, 1H), 7.19-7.39 (m, 3H), 7.45 (d, J=8.40 Hz, 1H). MS (ESI, pos. ion) m/z 332 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][NH:8]1.Br[CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29]([O:31][CH3:32])=[O:30].CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH:28]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(CC2NCCCc3cc(OC)c(OC)cc32)cc1OC
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
A mixture of 1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (1.10 g, 3.08 mmol), TEA (1.3 ml, 9.33 mmol), and methyl α-bromophenylacetate (487 μl, 3.09 mmol) in anhydrous toluene (13 ml) was stirred at reflux for 17 h under nitrogen. After cooling, the reaction mixture was dissolved in CH2Cl2 (40 ml), washed with H2O (15 ml), and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt/hexane: 1/1) gave the title compound as a mixture of stereoisomers (1.34 g, 2.65 mmol, 86%, yellow oil).
Reaction SMILES: [C:1]([C:3]1(O)[CH2:12][CH2:11][CH2:10][CH2:9][C:4]21[CH2:8][CH2:7][CH2:6][CH2:5]2)#[CH:2].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([C:3]1[C:4]2([CH2:9][CH2:10][CH2:11][CH:12]=1)[CH2:8][CH2:7][CH2:6][CH2:5]2)#[CH:2]
Reactant: C#CC1(O)CCCCC12CCCC2
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC1=CCCCC12CCCC2
Temperature: 87.5 °C
Yield: 76.7 %

Procedure:
At 20-27° C., a solution of 6-ethynylspiro[4.5]decan-6-ol (180 g, 1 mol) in pyridine (1 l) was treated dropwise with POCl3 (207 g, 2 mol). The resulting mixture was heated for 5.5 h heating at 85-90° C., poured into ice and extracted twice with pentane (800 and 300 ml). The combined organic phases were washed twice with water (500 ml), with a saturated aqueous solution of NaCl (300 ml), dried (MgSO4), and concentrated. Short-path Vigreux-distillation (8 mbar, head temperature: 85° C.) of the crude product (146 g) gave 6-ethynylspiro[4.5]dec-6-ene (122.9 g, 76%).
Reaction SMILES: Cl.[CH2:2]([N:20](C)[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:31](O)C>>[CH2:2]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][CH3:31])=[CH:25][CH:26]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCNc1ccc(NC)cc1

Procedure:
100 ml 2N hydrochloric acid is added to a solution of which 60.6 g (0.15 mol) N, N-octadecylmethyl-p-nitroaniline is dissolved into 500 ml ethyl alcohol. 52.5 g (0.13 mol) N, N-octadecylmethyl-p-phenylenediamine is obtained after adding 48.8 g (0.75 mol) zinc dust to the solution and heat and reflux it for one hour.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[O:22]1[C:26]2[CH:27]=[CH:28][C:29](B(O)O)=[CH:30][C:25]=2[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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]>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[C:4]4[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=3)[NH:7][CH:6]=[C:5]4[CH:14]3[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]3)=[CH:30][C:25]=2[CH2:24][CH2:23]1
Reactant: OB(O)c1ccc2c(c1)CCO2
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccc3c(c2)CCO3)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Reaction time: 0.3 h
Yield: 20.5 %

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (30 mg, 0.081 mmol), 2,3-dihydro-1-benzofuran-5-ylboronic acid (26.5 mg, 0.162 mmol), and K2CO3 (33.7 mg, 0.242 mmol) in 1,4-dioxane (0.36 mL) and water (0.180 mL) was degassed in a Biotage microwave vial for 10 min. PdCl2(dppf) (5.91 mg, 8.08 μmol) was added, the vial was sealed, and the reaction was heated at 100° C. (bath temp) for 5 min in a Biotage microwave oven at high absorption. EtOAc (3 mL) and water (1 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4×2 mL). The combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), and concentrated under a stream of nitrogen at 50° C. The crude product was dissolved in DMSO (1.2 mL), filtered through a 0.2 mm acrodisc, and purified on a Gilson HPLC (XBridge C18 5 mm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C., giving 6.8 mg (20%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][NH:21][C:20](=O)[C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.O.C([O-])(O)=O.[Na+]>C1COCC1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:33])[C:16]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[CH3:32])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1C(=O)NCCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1CNCCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of intermediate 40a (15.6 g) in anhydrous THF (94 m[), at 0° C., under N2, BH3 THF 1M/THF (154 ml) was added. The solution was heated at reflux for 3 hr. HCl 37% (54 ml) was slowly added maintaining the reaction mixture in an ice-bath and the reaction mixture was stirred at rt for 1 hr. Water was then added (125 ml) and solid NaHCO3 (62.4 g) was added portionwise until a pH of 6.5. The aqueous phase was extracted with Et2O (4×160 ml) and the combined organic extracts were dried over Na2SO4, the solids were filtered and evaporated to leave a colourless oil which was purified by flash chromatography (silica gel, EtOAc/Methanol 7/3). The obtained product was suspended in Et2O (220 ml) and washed with NaHCO3 sat. (2×36 ml). The combined organic phases were dried (Na2SO4) and evaporated to give the title compound as white foam (8.7 g.).
Reaction SMILES: [CH3:1][C:2](=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[C:8]([NH:12][NH2:13])([CH3:11])([CH3:10])[CH3:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:8]([NH:12][N:13]=[C:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH3:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)NN
Reactant: CC(=O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC(=NNC(C)(C)C)C(C)(C)C

Procedure:
To a solution of 5 g. (0.05 m.) pinacolone in 50 ml. benzene was added 5 g. (0.057 m) tert.-butylhydrazine and a spatula tip of para-toluenesulfonic acid. The flask was fitted with a Dean Stark trap and the reaction refluxed until 0.9 ml. (0.05 m.) of water was azeotroped off. The solution was cooled down and the benzene stripped off leaving 8.5 g. (100%) of a white fluffy solid. The infra-red spectrum of the solid was consistent with the structure of the proposed compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:43])[C:28]([C@@H:30]4[CH2:35][CH2:34][CH2:33][CH2:32][N:31]4C(OC(C)(C)C)=O)=[O:29])[CH2:23][CH2:22]3)=[C:17]([CH3:44])[C:16]=2[CH3:45])=[CH:11][CH:10]=1>C(Cl)Cl>[ClH:1].[ClH:1].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[N:19][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]([CH3:43])[C:28]([C@@H:30]4[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]4)=[O:29])[CH2:25][CH2:26]3)=[C:17]([CH3:44])[C:16]=2[CH3:45])=[CH:11][CH:10]=1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)[C@@H]3CCCCN3C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)[C@@H]3CCCCN3)CC2)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add 4 M HCl in 1,4-dioxane (1.00 mL, 4.00 mmol) to a solution of (S)-tert-butyl 2-((1-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)piperidin-4-yl)(methyl)carbamoyl)piperidine-1-carboxylate (80 mg, 0.152 mmol) in CH2Cl2 (2 mL). Stir the resulting mixture for 4 h at ambient temperature. Concentrate under reduced pressure and dry the residue in a vacuum oven at 45° C. to provide the title compound as pale yellow foam (79 mg, quantitative). ES/MS m/z 426.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C)[CH:14]=[CH:15][C:16]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)=O>C(O)(=O)C>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]1[N:3]2[CH:4]=[N:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[CH:14][CH:15]=1
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: CCOC(=O)c1[nH]cnc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c(-c3cccs3)ccnc12

Procedure:
A mixture of 1.55 g. (0.01 mols) of ethyl 4-amino-5-imidazolecarboxylate and 1.81 g. (0.01 mols) of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (prepared as described in Example 1, Part A) in 25 ml. of glacial acetic acid can be refluxed for 16 hours, then cooled and evaporated to dryness in vacuo. The residue can be dissolved in dichloromethane and passed through a short column of hydrous magnesium silicate. The effluent can be refluxed on a steam bath with a slow constant addition of n-hexane. At the first appearance of crystallization, heating should be curtailed and the solution allowed to cool. The precipitated material can be collected by filtration to produce ethyl 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)=[O:8].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([OH:9])=[O:11])=[C:6]([C:7]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[O:8])[CH:12]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NCCCCc1cccnc1
Product: O=C(O)c1ccc(Cl)cc1C(=O)NCCCCc1cccnc1

Procedure:
When 5-chlorophthalic anhydride was reacted with 4-(3-pyridinyl)butylamine by the procedure of Example 12, the above compound, mp 152°-154° C. was obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([NH2:22])([CH2:16]4)[CH2:14]3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]([N:34]1[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]1[C:40]#[N:41])=[O:33]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:21][CH:17]4[CH2:16][C:15]([NH:22][CH2:31][C:32]([N:34]5[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]5[C:40]#[N:41])=[O:33])([CH2:14]2)[CH:19]([CH2:18]4)[CH2:20]3)=[CH:11][CH:12]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a stirred mixture of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.03,7]nonan-3-amine (as obtained in example 8 Step II) (0.17 g, 0.5 mmol) and K2CO3 (0.21 g, 1.5 mmol) in DMSO (2 mL) at an ice bath temperature was added (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.1 g, 0.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile as an off-white powder (0.09 g) in 37% yield as a 3:1 mixture of two rotomers. IR cm−1 3438, 2953, 2776, 1673, 1518, 1427, 1301, 1135, 1078, 955; m/z (M+1) 487; 1H NMR (CDCl3) 300 MHz δ 7.25 (d, J=6.2 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 5.42 (d (br), J=51.0 Hz, 0.8H), 5.34 (d (br), J=50.4 Hz, 0.2H), 5.15 (d, J=10.2 Hz, 0.2H), 4.98 (d, J=7.4 Hz, 0.8H), 4.0-3.50 (m, 4H), 3.76 (t, J=6.5H, 2H), 3.35 (t, J=6.5 Hz, 2H), 2.80-2.28 (m, 6H), 2.15-1.58 (m, 10H).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:33][C:34]([O:37][C:38]([NH:40][C@H:41]([C@H:43]1[CH2:48][CH2:47][C@H:46]([C:49](O)=[O:50])[CH2:45][CH2:44]1)[CH3:42])=[O:39])([CH3:36])[CH3:35]>>[CH3:31][O:30][C:29]([NH:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]2[NH:18][C:17]([C@@H:14]3[CH2:13][C@H:12]([CH:9]4[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]4)[CH2:16][N:15]3[C:49]([C@H:46]3[CH2:45][CH2:44][C@H:43]([C@@H:41]([NH:40][C:38](=[O:39])[O:37][C:34]([CH3:36])([CH3:35])[CH3:33])[CH3:42])[CH2:48][CH2:47]3)=[O:50])=[N:21][CH:20]=2)=[CH:27][CH:26]=1)=[O:32]
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)[C@H]3CC[C@H]([C@H](C)NC(=O)OC(C)(C)C)CC3)[nH]2)cc1

Procedure:
Following the procedure described in Example 8, the compound prepared in Example 66 was treated with trans-4-[(1S)-1-({[(2-methyl-2-propanyl)oxy]carbonyl}amino)ethyl]cyclohexanecarboxylic acid to give the title compound as a light brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7])=O.CC(O)=O.[CH2:17]([NH:19][CH3:20])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CN1C(=O)CCC1>[CH2:17]([N:19]([CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:20])[CH3:18]
Reactant: Cc1cc(C=O)cc(C(=O)O)c1
Reactant: CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCN(C)Cc1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a solution of 3-formyl-5-methyl-benzoic acid (2.83 g, 17.2 mmol) in DCM (100 mL) and NMP (15 mL), AcOH (3.17 g, 51.7 mmol) and N-ethyl-methylamine (4.08 g, 69.0 mmol) is added. The mixture is stirred at rt for 45 min before NaBH(OAc)3 (8.12 g, 34.5 mmol) is added. The mixture is stirred at rt for 16 h before it is concentrated. The remaining residue is dissolved in MeCN and DMF and filtered over a paper filter. The filtrate is separated by prep. HPLC (Waters XBridge 50×50 mm+100×50 mm, eluting with a gradient of acetonitrile in water containing 0.5% of sat. aq. ammonia) to give the title compound as a white solid (1.67 g). LC-MS*: tR=0.46 min, [M−H]−=206.28; 1H NMR (D6-DMSO): δ 1.03 (t, J=7.3 Hz, 3H), 2.09 (s, 3H), 2.35 (s, 3H), 2.39 (q, J=7.0 Hz, 2H), 3.46 (s, 2H), 7.31 (s, 1H), 7.63 (s, 1H), 7.67 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1.[I-].[Na+].C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O.CCOCC>[CH:12]1([CH2:11][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=2)[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: C#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOCC
Solvent: CC(C)=O
Product: C#Cc1cccc(OCC2CC2)c1
Yield: 84.2 %

Procedure:
To a solution of 3-ethynylphenol (1.18 g, 10.0 mmol) in acetone (30 mL) is added (bromomethyl)cyclopropane (1.02 mL, 10.0 mmol), sodium iodide (0.75 g, 5.0 mmol) and Cs2CO3 (6.52 g, 20.0 mmol) at room temperature. After refluxing over night, the reaction mixture is cooled, diluted with Et2O (300 mL) and pass through a thin layer of silica gel. The solution is concentrated. The resultant residue is purified by chromatography (silica gel, EtOAc/hexane: 1/99) to give the title compound (1.45 g, 84%) as an oil. MS(+) APPI: 173 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1.[CH3:28][N:29]([CH3:34])[C:30](=[O:33])[CH:31]=[CH2:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:28][N:29]([CH3:34])[C:30](=[O:33])/[CH:31]=[CH:32]/[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]2[CH2:23][C:22]([CH3:24])([CH3:25])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)[N:12]=1
Reactant: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(Cl)cccc34)n2)CC(C)(C)N1
Reactant: C=CC(=O)N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CN(C)C(=O)/C=C/c1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared by the general Heck procedure described in Example 256, using the SEM-protected intermediate of Example 228 and N,N-dimethyl-acrylamide, followed by TBAF deprotection of the SEM group.
Reaction SMILES: [C:1]([S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12)(=O)[CH3:2].[Br:13]CCO>>[Br:13][CH2:2][CH2:1][S:4][C:5]1[N:6]=[CH:7][N:8]2[CH:12]=[CH:11][S:10][C:9]=12
Reactant: CC(=O)Sc1ncn2ccsc12
Reactant: OCCBr
Product: BrCCSc1ncn2ccsc12

Procedure:
The procedure of Synthesis Example 11b) was repeated, except that 990 mg of 7-acetylthioimidazo[5,1-b]thiazole and 0.461 ml of 2-bromo ethanol were used as the starting compounds. Thus, 1.06 g of 7-(2-bromoethyl)thioimidazo[5,1-b]thiazole was prepared.