Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([NH2:20])([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH:7]2[CH2:6]1)=[O:4].Cl[CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25].C(=O)([O-])[O-].[K+].[K+]>ClCCl.CN(C)C=O>[CH3:21][N:2]([CH3:1])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([NH:20][CH2:23][C:24]([N:26]3[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]3[C:32]#[N:33])=[O:25])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reactant: CN(C)C(=O)N1CC2CC(N)(Cc3ccccc3)CC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)CC2C1

Procedure:
5-Amino-5-benzyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14f (0.1 g, 0.35 mmol) was dissolved in 4 mL of the solvent mixture of dichloromethane/N,N-dimethylformamide (V/V=1/1) followed by addition of (2S,4S)-1-(2-chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile 13g (66.5 mg, 0.35 mmol) and potassium carbonate (49 mg, 0.35 mmol). The reaction mixture was reacted at 40° C. for 12 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-5-[(2-((2S,4S)-2-cyano-4-fluoro-pyrrolidin-1-yl)-2-oxo-ethylamino]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14g (87 mg, yield 56%) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:46]=[CH:47][C:48]=1B1OC(C)(C)C(C)(C)O1)[O:31][CH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[CH2:35][CH2:34]1.C(N)(=O)CCC>>[F:27][C:28]1[CH:29]=[C:30]([O:31][CH2:32][C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[CH2:35][CH2:34]2)[CH:46]=[CH:47][C:48]=1[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[C:4](=[O:26])[CH:3]=1
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO[C@@H]1CCCCO1)S(C)(=O)=O
Reactant: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2F)OC1(C)C
Agent: CCCC(N)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
The title compound (366 mg, 65.5 mmol) was prepared from (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-[(2R)-tetrahydro-2H-pyran-2-yloxy]butanamide (0.410 g, 8.23 mmol) and (+/−)-2-[(trans-4-{[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (0.358 g, 8.23 mmol) by a procedure analogous to that described for (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-Netrahydro-2H-pyran-2-yloxy)butanamide Example 8, Step E. LCMS m/z 677.8 (M−1)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl[CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:11][CH:12]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 24b) from 4-phenylphenol (0.916 g), ethanol (10 ml), sodium hydroxide (0.215 g), water (5 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g; from Example 24a) above) to give a yellow oil. This was purified by column chromatography over silica eluting with dichloromethane:ethanol (95:5) to give the title compound as a pale yellow gum which solidified on standing (0.307 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.C([Li])CCC.[O:27]1[CH2:30][C:29](=[O:31])[CH2:28]1.CO>C1COCC1>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2([OH:31])[CH2:30][O:27][CH2:28]2)=[CH:3][CH:4]=1
Reactant: O=C1COC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C2(O)COC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
A solution of 5-bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine (100 mg, 0.29 mmol) THF (3 mL) was treated with n-butyl lithium (1.6 M in hexanes, 0.18 mL, 0.29 mmol) at −75° C. Then a solution of 3-oxetanone (22.0 mg, 0.29 mmol) in THF (1 mL) was added and the mixture was stirred for 10 min. Methanol was then added and the mixture was allowed to warm to room temperature. Purification by chromatography (SiO2, ethylacetate/heptane 2:8 to 1:1) afforded the title compound (65 mg, 66%) as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2.[C:17](O[Na])([CH3:19])=[O:18].C(OC(=O)C)(=O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[O:12][C:17](=[O:18])[CH3:19])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2
Reactant: C=CCc1c(O)c(C)cc2ccc(=O)oc12
Reactant: CC(=O)O[Na]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C=CCc1c(OC(C)=O)c(C)cc2ccc(=O)oc12
Yield: 129.2 %

Procedure:
In such a manner a mixture of 6-methyl-7-hydroxy-8-allylcoumarin (VII) (6.3 g), anhydrous AcONa (1.5 g) and acetic anhydride (40 ml) was refluxed for 1 h. The reaction mixture was gently diluted with water (40 ml), refluxed for 10 min and then poured into H2O (300 ml) yielding a precipitate, which was collected by filtration and washed several times with H2O. The dried product was crystallized from MeOH yielding 6-methyl-7-acetoxy-8-allylcoumarin (X) (6.1 g; m.p. 110°-11° C.). ##STR16##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:12])[C:10]=1[Cl:11])[C:7](=[O:13])[C:6]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:14])[CH2:5]2.C(=O)([O-])[O-].Br[CH2:25][C:26]([O:28]CC)=[O:27]>CC(C)=O>[Cl:11][C:10]1[C:9]([Cl:12])=[C:8]2[C:4]([CH2:5][C:6]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)([CH3:14])[C:7]2=[O:13])=[CH:3][C:2]=1[NH:1][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: CC1(C2CCCC2)Cc2cc(N)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(NCC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 8 h
Yield: 15.7 %

Procedure:
A mixture of 5-amino-6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1H-inden-1-one (800 mg), postassium carbonate (440 mg), and ethyl bromoacetate (540 mg) in acetone (20 ml) is heated at reflux overnight. The reaction mixture is filtered, the acetone is distilled at reduced pressure and the residual oil is dissolved in a mixture of ethanol (5 ml) and methylene chloride (5 ml) and treated with 10 N sodium hydroxide (2 ml). The mixture is stirred overnight, the solvents are distilled at reduced pressure and the residue is treated with water, then filtered and acidified with hydrochloric acid and extracted with ethyl acetate. Evaporation of the ethyl acetate gives 150 mg of [(6,7-dichloro-2-cyclo-pentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)amino]acetic acid which melts at 199°-200° C. after recrystallization from chloroform-hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1.C(O)(=O)C.CO[CH:30]1[CH2:34][CH2:33][CH:32](OC)O1>Cl.O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH:30]=[CH:34][CH:33]=[CH:32]5)=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(N)cc4)[nH]c3cc21
Reactant: COC1CCC(OC)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(-n5cccc5)cc4)[nH]c3cc21
Reaction time: 20 h

Procedure:
3.06 g. 8,8-dimethyl-2-(4-aminophenyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolin-6-one (see Example 38) were allowed to stand for 20 hours at 25° C. with 30 ml. glacial acetic acid, 5 ml. water, 2 drops of concentrated hydrochloric acid and 1.32 ml. 2,5-dimethoxytetrahydrofuran. The reaction mixture was then washed with 100 ml. water. After crystallization from ethanol, there was obtained 0.8 g. of the title compound; m.p. 329°-350° C. (decomp.).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:16])[CH2:6][C:7]#[C:8][CH2:9][O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])(=[O:3])[CH3:2].[H][H]>[Ni].C(O)C>[C:1]([O:4][C@H:5]([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(C)OCC#CC[C@@H](C)OC(C)=O
Agent: [Ni]
Solvent: CCO
Product: CCOC(C)OCCCC[C@@H](C)OC(C)=O
Yield: 101.3 %

Procedure:
Alternatively, hydrogenation was run using a mixture of Raney nickel (10 g of slurry) and 5-(R)-acetoxy-1-ethoxyethoxy-2-hexyne (40 g, 0.17 mole) in ethanol (100 ml). The mixture was shaken with hydrogen gas (60 psi) on a Parr shaker for 5 hours. After filtration of the catalyst, the filtrate was evaporated under vacuum. Residual oil was dissolved in hexanes (100 ml) and the mixture was filtered to remove suspended particles. Evaporation of the solvent under reduced pressure provided 5-(R)-acetoxy-1-ethoxyethoxyhexane (40 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][N:8]([CH2:30][C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9][C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]COCC[Si](C)(C)C)=[CH:16][C:15]=1[Cl:29])[CH3:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[C:1]([O:5][C:6](=[O:44])[CH2:7][N:8]([CH2:30][C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:9][C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[Cl:29])[CH3:13])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(O)cc1Cl
Temperature: 50 °C
Reaction time: 96 h
Yield: 90.6 %

Procedure:
To a solution of tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl){2-[(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)(methyl)amino]-2-oxoethyl}amino]methyl}benzoate (805 mg) in tetrahydrofuran (16.1 mL) was added a 1 M solution of tetra-n-butylammonium in tetrahydrofuran (3.72 mL), followed by stirring at 50° C. for 4 days. To a reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl){2-[(2-chloro-4-hydroxyphenyl)(methyl)amino]-2-oxoethyl}amino]methyl}benzoate (583 mg).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[O-]C1C=CC=CC=1.[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)(=[O:23])[CH3:22]>CN(C)C=O>[C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[CH:12][CH:11]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCCCCCl
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1ccc(C(C)(C)C)cc1

Procedure:
To a stirred slurry of 1.6 g sodium hydride (as 50% dispersion in oil) in 50 ml dry dimethyl formamide was added, dropwise, a solution of 5.0 g p-tert-butylphenol (33.3 mmoles) in 50 ml dry dimethyl formamide and the solution stirred under nitrogen until the phenoxide had totally formed. To the phenoxide was added a solution of 5.0 g 4-chlorobutyl acetate (33.3 mmoles) in 50 ml dry dimethyl formamide and the solution was stirred for fourteen hours. The reaction mixture was partitioned between water/toluene. The organic layer was removed, washed with water, then 1 N sodium bicarbonate. The organic layer was removed, dried and evaporated to an orange oil, 5.6 g. The oil was chromatographed on 500 g, 90 to 200 mesh silica gel (CH2Cl2 eluent) yielding pure 4-(p-tert-butylphenoxy)-butyl acetate.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH:14][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: CC(N)c1sc2ccccc2c1-c1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1sc2ccccc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(3-phenylbenzo[b]thiophen-2-yl)ethylamine from Example 23 (160 mg, 0.63 mmol), 6-chloro-9H-purine (98 mg, 0.63 mmol) and DIPEA (0.16 mL, 0.95 mmol) in n-butanol (1.3 mL) was stirred in a sealed vial for 3 days at 120° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-6% MeOH in DCM) and then triturated with EtOAc affording 101 (105 mg, 45%). LCMS: RT 4.33 min [M+H]+ 372.1. 1H NMR (DMSO, 400 MHz): δ 8.21 (1H, s), 8.16-8.10 (2H, m), 7.92-7.86 (1H, m), 7.66-7.54 (4H, m), 7.50-7.44 (1H, m), 7.37-7.26 (3H, m), 5.76 (1H, s), 1.50 (3H, d, J=6.94 Hz)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH3:14][N:15]1[C:19]2[CH:20]=[CH:21][C:22]([N+]([O-])=O)=[CH:23][C:18]=2[N:17]([CH3:27])[C:16]1=[O:28]>CO.[Pd]>[CH3:27][N:17]1[C:18]2[CH:23]=[CH:22][C:21]([NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=3)=[CH:20][C:19]=2[N:15]([CH3:14])[C:16]1=[O:28]
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Reactant: Cn1c(=O)n(C)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(=O)n(C)c2cc(NCCc3ccc(C(F)(F)F)nc3)ccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
A solution of (6-trifluoromethyl-pyridin-3-yl)-acetonitrile (223 mg, 1.21 mmol, prepared as per example 1, step 1) and 1,3-dimethyl-5-nitro-1,3-dihydro-benzoimidazol-2-one (240 mg, 2.41 mmol, commercially available) in MeOH (10 mL) was treated with NH4OAc (13.00 mmol) and 10% Pd/C (200 mg) and stirred at 60° C. for 72 h. Filtration, concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 60:40) afforded the title compound (216 mg, 25%) as a light yellow oil. MS m/e: 351.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8](O)[CH:9]=[CH2:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]([F:7])([F:6])[C:3]([O:5][CH2:10][CH:9]=[CH2:8])=[O:4]
Reactant: C=CCO
Reactant: O=C(O)C(F)(F)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)C(F)(F)Cl

Procedure:
In a 1.5 liter sulfonation flask with a water separator, 294.0 g (2.25 mol) of chlorodifluoroacetic acid (pure, from Fluka AG) and 228.0 g (3.93 mol) of allyl alcohol are dissolved in 1 liter of chloroform and kept under reflux for 17 hours in the presence of 11.25 g of p-toluenesulfonic acid (0.06 mol), 41 ml of H2O separating out. The yellow reaction solution is washed twice with H2O and 3 times with saturated aqueous NaHCO3 solution, dried over MgSO4 and distilled under normal pressure through a Vigreux column. Yield: 306.0 g (80%) of a colourless oil of boiling point 98°-100° C./988 mbar.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([Br:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]1[C@@H:21]([Br:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O[C@H]1C[C@@H]2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](C(C)=O)CC[C@@H]34)[C@@]2(C)C[C@@H]1Br
Reaction time: 8 h

Procedure:
A solution of 3α-hydroxy-2β-bromo-5α-pregnan-20-one (8.5 g.) in pyridine (25 ml.) was treated with acetic anhydride (12.5 ml.), and the mixture was allowed to stand at room temperature overnight. The reaction mixture was poured into water and the product was extracted with methylene chloride. The extract was washed with water, dried (Na2SO4) and evaporated. A portion (582 mg.) of the residue (8.5 g.) was purified by preparative thin layer chromatography and crystallisation from iso-propyl ether to give the title compound (70 mg.), m.p. 142°-146°, [α]D + 120.9°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[C:5]2=[CH:4][CH:3]=1.[CH3:30][Mg]I>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: O=CCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Reactant: C[Mg]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Temperature: -20 °C
Reaction time: 4 h
Yield: 22.8 %

Procedure:
In a 100 mL dry flask, 4-{5-chloro-2-[1-cyclopropyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl]-1H-imidazo[4,5-b]pyridin-1-yl}butanal 67-1 (1.5 g, 3.6 mmol) was dissolved in dry THF (50 mL) and cooled until −20° C. under N2 atmosphere. An excess methylmagnesium iodide (3M in THF) (1.8 mL, 5.5 mmol, 1.5 eq.) was then gently added dropwise to the cooled solution via syringe. The solution was warmed up until ambient temperature and stirred for 4 hours. The solution was diluted with 30 mL NaHCO3 solution and extracted with EtOAC (30 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The crude was purified on RP SunFire Prep column (C18 OBD-10 μm,30×150 mm), using a 0.25% NH4HCO3 solution in water-MeOH solution to give 350 mg (22%) of 3-{[5-chloro-1-(4-hydroxypentyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-1-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (67) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.05 (m, 2 H) 1.13-1.22 (m, 5 H) 1.43-1.57 (m, 2H) 1.77-1.91 (m, 2 H) 2.11 (br. s, 1 H) 2.89-2.98 (m, 1 H) 3.81-3.90 (m, 1 H) 4.32-4.50 (m, 2 H) 5.40 (s, 2 H) 7.13 (dd, J=5.27, 0.75 Hz, 1 H) 7.23 (d, J=8.53 Hz, 1 H) 7.65 (d, J=8.28 Hz, 1 H) 8.34 (d, J=5.27 Hz, 1 H) 8.75 (s, 1 H); LCMS m/z=427 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH2:20]1[O:29][C:28]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[O:29]1[C:28]2[CH:27]=[CH:26][C:24]([NH:25][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:23][C:22]=2[O:21][CH2:20]1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)OCO4)c2cc1OCC
Temperature: 100 °C
Yield: 96.4 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 258 mg (1.88 mM) of 3,4-(methylenedioxy) aniline in 10 ml of ethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 526 mg of 4-(Benzo[1,3]dioxol-5-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a tan solid: mass spectrum (electrospray, m/e): M+H 378.0, mp=200-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][NH2:30]>>[NH2:30][CH2:29][CH2:28][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: NCCCl
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1N1CCN(C(=O)c2cn(CCN)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH:18](C(OCC)=O)[C:17](=[O:24])[NH:16][C:15]2=[O:25])[C:7]1=[O:26].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:18][C:17](=[O:24])[NH:16][C:15]2=[O:25])[C:7]1=[O:26]
Reactant: CCOC(=O)C1C(=O)NC(=O)C12C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Yield: 33.4 %

Procedure:
A mixture of 1'-(3,4-dichlorobenzyl)-4-ethoxycarbonyl-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione(8.2 g.) and acetic acid (50 ml.) was heated under reflux for 22 hours. The solution obtained was cooled and poured into water (300 ml.). The solid which formed was collected by filtration and recrystallised from methanol to give 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (2.3 g.), m.p. 203°-204° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[C:55](=[O:70])[NH:56][C:57]([CH3:69])=[CH:58][C:59]=1[CH2:60][O:61][Si](C(C)(C)C)(C)C.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:52][CH2:53][C:54]2[C:55](=[O:70])[NH:56][C:57]([CH3:69])=[CH:58][C:59]=2[CH2:60][OH:61])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CN)c(=O)[nH]1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(CO)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.6 %

Procedure:
To a solution of 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid (2.3 g, 7.5 mmol) in DMSO (30 mL), PyBOP (5.82 g, 11.20 mmol) was added and reaction stirred at room temperature for 15 min. 3-(Aminomethyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2(1H)-one (2.52 g, 8.96 mmol) was then added and reaction mixture stirred overnight. On completion, water was added and the resulting precipitate filtered and washed with water. This solid was then stirred with acetonitrile for 10 min and filtered again to obtain 6-bromo-1-cyclopentyl-N-((4-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.4 g, 40.9%).