Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:19]([Cl:30])=[CH:18][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([NH:17][C:16]1[CH:18]=[C:19]([Cl:30])[C:20]([O:22][C:23]([F:29])([F:28])[C:24]([F:25])([F:26])[F:27])=[CH:21][C:15]=1[Cl:14])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(OC(F)(F)C(F)(F)F)cc1Cl
Reaction time: 10 h

Procedure:
3.4 g of 2,6-difluorobenzoyl isocyanate, dissolved in 10 ml of dry toluene, are added at room temperature and with the exclusion of moisture to 5.6 g of 2,5-dichloro-4-pentafluoroethoxyaniline dissolved in 40 ml of dry toluene, and the batch is stirred for 10 hours. Approximately 60% of the solvent is then removed. The precipitate formed is filtered off with suction, washed with hexane and dried in vacuo. The title compound of formula ##STR15## is obtained in the form of colourless crystals; m.p. 178°-179° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([C:27]([NH2:29])=[O:28])[NH2:26]>>[CH3:24][N:25]([C:27]([NH2:29])=[O:28])/[N:26]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: CN(N)C(N)=O
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: C/C(=N\N(C)C(N)=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared as a white solid in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and 1-methylhydrazine-carboxamide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.68 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 8.03 (s, 1H), 8.01 (d, 1H), 7.82 (dd, 1H), 7.53 (dd, 1H), 6.75 (s, 2H), 6.21 (s, 2H) 2.50 (s, 3H), 2.49 (s, 3H). LCMS (method B): [MH]+=376, tR=1.88 min.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: COc1ccc(OCCCCCCCCI)c(Cl)c1
Reactant: CCOP(=O)(CC(C)=O)OCC
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCCCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 25 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)8, R is C2H5, R' is CH3CO] was prepared from 0.38 g of lithium hydride, 9.5 g of diethyl acetonylphosphonate and 19.4 g of 8-(2-chloro-4-methoxyphenoxy)octyl iodide according to the procedure of Example 12(b). The product was chromatographed on Florisil to give 5.67 g of diethyl [1-acetyl-9-(2-chloro-4-methoxyphenoxy)nonyl]phosphonate as a light yellow oil; MIC vs. herpes simplex type 2=12 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH2:25])[CH:16]=[CH:17][C:18]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1>>[Cl:10][C:4]1[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=[C:2]([NH:25][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[C:13]([O:12][CH3:11])[CH:14]=2)[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(CO)cc(Cl)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 2,6-dichloropyridin-4-methanol (53 mg, 0.3 mmol) and 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol). The reaction was heated for 16 h to reflux. Obtained as a pale-yellow solid (25 mg, 24%) after column chromatography on silica gel using dichloromethane/methanol (9:1 v/v) as eluent.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:22])[NH:12][C:11]1=[O:23])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Cl[C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>>[CH2:1]([NH:7][C:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13](=[O:22])[N:12]([C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[C:11]1=[O:23])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC(C)COC(=O)Cl
Reactant: CCCCCCNC(=O)n1cc(-c2ccccc2)c(=O)[nH]c1=O
Product: CCCCCCNC(=O)n1cc(-c2ccccc2)c(=O)n(C(=O)OCC(C)C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 39 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 24, starting from N-hexyl-2,4-dioxo-5-phenyl-pyrimidine-1-carboxamide (Example 14) (0.05 g, 0.17 mmol); 9.0 equivalents of isobutyl chloroformate were used herein. Another portion of isobutyl chloroformate (9.0 equivalents) was added after 5 hrs and the reaction stirred at room temperature for 15 hrs. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 90:10) to afford the title compound (0.043 g, 39%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.90 (t, J=6.8 Hz, 3H), 1.02 (d, J=6.8 Hz, 6H), 1.29-1.41 (m, 6H), 1.57-1.65 (m, 2H), 2.12 (h, J=6.7 Hz, 1H), 3.41 (td, J=7.1, 5.7 Hz, 2H), 4.27 (d, J=6.7 Hz, 2H), 7.36-7.45 (m, 3H), 7.53-7.57 (m, 3H), 8.57 (s, 1H), 8.96 (t, J=5.0 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.14, 18.96, 22.65, 26.63, 27.84, 29.26, 31.52, 41.65, 76.42, 116.58, 128.58, 128.78, 128.92, 131.19, 135.34, 149.45, 149.54, 149.78, 159.35. MS (ESI) m/z: 416 [M-H]+.
Reaction SMILES: [CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][OH:7].[CH2:9]([O:11][CH:12]=[CH2:13])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(N(CC)CC)C>[CH3:1][S:2][C:3](=[S:8])[NH:4][CH2:5][CH2:6][O:7][CH:9]([O:11][CH2:12][CH3:13])[CH3:10]
Reactant: CSC(=S)NCCO
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(C)OCCNC(=S)SC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice cold and stirred mixture of N-(2-hydroxyethyl)dithiocarbamic acid methyl ester (1.513 g) and ethoxyethylene (1.92 ml) is added toluene-p-sulfonic acid monohydrate (9.5 mg). After stirring for 30 minutes at room temperature, the homogeneous solution is mixed with triethylamine (8 μl) and concentrated under reduced pressure to yield N-[2-(1-ethoxyethoxy)ethyl]dithiocarbamic acid methyl ester (2.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)/[CH:9]=[CH:10]/[N:11]([CH3:13])[CH3:12])[N:3]=1>C(O)C.[Pt]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:3]=1
Reactant: CN(C)/C=C/C(c1ccc(Cl)cc1)c1cccc(Br)n1
Agent: [Pt]
Solvent: CCO
Product: CN(C)CCC(c1ccc(Cl)cc1)c1cccc(Br)n1
Reaction time: 96 h

Procedure:
A solution of E-2-bromo-6-(1-(4-chlorophenyl)-3-dimethylaminoallyl)pyridine (vide supra (2.0 g) in absolute ethanol (150 mL) was stirred under hydrogen with 10% Pt/C (0.86 g) for 48 hr. The reaction mixture was filtered through Celite and the reduction continued with fresh catalyst (0.67 g) for an additional 96 hr. Filtration through Celite and concentration under reduced pressure gave an oil which was chromatographed on silica gel (Waters Prep 500) with 3:1/methanol:methylene chloride. This provided 2-bromo-6-(1-(4-chlorophenyl)-3-dimethylaminopropyl)pyridine (0.66 g) as an oil:TLC Rf 0.22 (silica gel, methanol).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[S:22][C:21]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:20][C:19]=1[Cl:29].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:19]1[CH:20]=[C:21]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[S:22][C:18]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: Clc1cc(-c2cccnc2)sc1Br
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccnc4)cc3Cl)c(C)nc12
Yield: 37 %

Procedure:
Using a procedure similar to Example 85 Method B Step C, from 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 2.30 mmol), 3-(5-bromo-4-chloro-thiophen-2-yl)-pyridine) (0.76 g, 2.76 mmol), Cs2CO3 (1.57 g, 4.83 mmol), PPh3 (0.11 g, 0.44 mmol) and Pd2(dba)3 (0.10 g, 0.11 mmol). The residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient) furnish the title compound (0.35 g, 0.85 mmol, 37%). Spectrum identical to Method A.
Reaction SMILES: C([O:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][C:10]([O:13][C:14](=[O:19])[CH2:15][O:16]C=O)([CH3:12])[CH3:11])=[O:6])=O>C(=O)(O)[O-].[Na+]>[OH:3][CH2:4][C:5]([O:7][CH2:8][CH2:9][C:10]([O:13][C:14](=[O:19])[CH2:15][OH:16])([CH3:12])[CH3:11])=[O:6]
Reactant: CC(C)(CCOC(=O)COC=O)OC(=O)COC=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(CCOC(=O)CO)OC(=O)CO
Reaction time: 72 h

Procedure:
The crude product (102) was combined with aqueous sodium bicarbonate solution (20 mL, 0.75 N) and stirred for 3 days. The compound was then extracted using ethyl acetate in three 20 mL portions. The organic phase was then evaporated and separated in a column to get a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.42 (s, 6H), 2.19 (t, 2H), 2.58 (s, 2H), 4.00 (s, 2H), 4.16 (s, 2H), 4.28 (t, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[O:7][C@H:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18])[O:9][C@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[CH:4]=1.C(N(CC)CC)C>CCO.[Pd]>[ClH:2].[C:11]1([C@@H:10]2[C:5]3[CH:4]=[CH:3][CH:27]=[CH:26][C:6]=3[O:7][C@H:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:18])[O:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CN(C)CCCNC(=O)[C@H]1Oc2ccc(Cl)cc2[C@@H](c2ccccc2)O1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)CCCNC(=O)[C@H]1Oc2ccccc2[C@@H](c2ccccc2)O1

Procedure:
cis-6-Chloro-4-phenyl-N-(3-dimethylaminopropyl)-1,3-benzodioxan-2-carboxamide hydrochloride (1.06 g, 2.59 mmole), triethylamine (0.526 g., 5.2 mmole) and 30% Pd on Celite (0.6 g) were mixed in abs EtOH (200 ml) and hydrogenated in a Parr apparatus for 21/2 hrs. (14 lb H2 uptake). Workup and treatment with HClg in the usual manner (see example 12) gave the product (0.7 g., 71.8% mp 178°-186° d) after recrystallization from i-PrOH:Et2O.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:23][C:24]([C:26]2[C:27]([CH3:38])=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:30]=2)=[O:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH2:10]1)#[N:2].[H-].[Na+].Br[CH2:42][C:43]([O:45]CC)=[O:44].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([N:23]([C:24]([C:26]2[C:27]([CH3:38])=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:30]=2)=[O:25])[CH2:42][C:43]([OH:45])=[O:44])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([OH:15])[CH2:13][CH2:14]1)#[N:2]
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)c(C#N)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)N(CC(=O)O)c1ccc(N2CCC(O)CC2)c(C#N)c1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
N-(3-Cyano-4-(4-tert-butyldimethylsilyloxypiperidin-1-yl)phenyl)-1-(4-fluorophenyl)-3-methylpyrazole-4-carboxamide (2.1 g) and sodium hydride (60% content, 0.2 g) were reacted in dimethylformamide (30 ml) under ice-cooling for 1 h. Dimethylformamide solution (10 ml) containing ethyl bromoacetate (1.0 g) was added and the mixture was stirred under ice-cooling for 1 h and, after allowed to warm to room temperature, stirred for another 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. To the residue were added tetrabutylammonium fluoride (2.0 g), tetrahydrofuran (20 ml) and acetonitrile (20 ml) and the mixture was stirred at 80° C. for 1 h. The solvent was evaporated under reduced pressure. To the residue was added dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A mixed solvent of toluene-ethyl acetate was added to the residue to allow crystallization. The crystals were recrystallized from hydrous isopropanol to give the title compound (0.2 g), melting point: 124–125° C.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8](C)([CH3:13])[O:9]2)[CH2:5][O:4]1.BrCC1OCC(O)C(O)CO1.C(=O)CC>>[Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][CH:8]([CH3:13])[O:9]2)[CH2:5][O:4]1
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Agent: OC1COC(CBr)OCC1O
Solvent: CCC=O
Product: CC1OC2COC(CBr)OCC2O1
Yield: 71 %

Procedure:
4-Bromomethyl-9-methyl-3,5,8,10-tetraoxabicyclo [5.3.0]decane was prepared in a similar way to 4-bromomethyl-9,9-dimethyl-3,5,8, 10-tetraoxabicyclo[5.3.0]decane starting from 132 mmol (30 g) of 2-bromomethyl-5,6-dihydroxy-1,3-dioxepane and from 0.816 mol (60 ml) of propionaldehyde, fractional distillation giving 25 g (71% yield) from 100° to 102° C. (0.4 mbar).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Yield: 74.5 %

Procedure:
A solution of 56 g of 4-nitrophenol, 90 g of methyl bromoacetate and 100 g of potassium carbonate in 500 ml of dimethylformamide was stirred at room temperature for 2 days. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was crystallized by trituration with hexane, to give 63.3 g of the title compound, melting at 98°-99° C.
Reaction SMILES: [BH4-].[Na+].[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([C:6]3=[O:13])[CH2:4]1)[CH2:10]2>CO.[Cl-].[Na+].O>[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH:6]3[OH:13])[CH2:4]1)[CH2:10]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1C2CC3CC1CN(C3)C2
Temperature: 0 °C

Procedure:
Sodium borohydride (0.7 g) is added to 20 ml of ice-chilled MeOH. Then 1.88 g (0.012 mole) of 1-azatricyclo[3.3.1.13,7 ]decane-4-one, in 20 ml MeOH, is added dropwise over 5 minutes. A further 0.8 g NaBH4 (total 1.5 g, 0.04 mole) is added portionwise over 5 minutes. The reaction is stirred in ice one-half hour more, and then 1 hour at room temperature. The reaction is diluted with 20 ml brine, and extracted into ether. The ether is dried over MgSO4 and stripped to dryness, to give 1 -azatricyclo-[3.3.1.13,7 ]decane-4-ol.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1.C(N(CC)CC)C>O1CCCC1.CN1CCN(C)C1=O>[C:1]([NH:7][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][C:20](=[O:23])[NH:21][N:22]=3)[CH:14]=2)[CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: CCCC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
Butyryl chloride (4.09 g) dissolved in 20 ml of tetrahydrofuran was added dropwise to 7.26 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 7.05 g of triethylamine suspended in 70 ml of 1,3-dimethyl-2-imidazolidinone. The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration, washed with water and dried. The crystals were recrystallized from ethyl acetate to obtain 7.47 g of 2-butyrylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[F:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[F:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: FC[C@@H]1CCCN1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCC[C@H]4CF)cc3c2)cc1

Procedure:
The product from Example 1C and the product from Example 164C were processed as described in Example 1D to provide the titled compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was run at 60° C. for 3 days, then worked up by pouring into toluene. The organic phase was extracted with 7:2:1 of water/N-methylpyrrolidinone/10% aqueous methanesulfonic acid, and the aqueous phase then covered with isopropyl acetate and adjusted to pH 11 with 50% aqueous NaOH. After shaking and separation of the layers, the isopropanol extract was saved, then combined with a second isopropanol extract of the aqueous layer. The combined isopropanol extract was washed three times with 5% aqueous NaHCO3, water, dried over magnesium sulfate, filtered, and concentrated in vacuo to a brown oil. The free base was converted to the mono-L-tartrate salt by addition of 1 equivalent of L-tartaric acid to the free base in ethanol. Two hours after removal of some of the ethanol under vacuum, the mixture deposited an off-white solid. The solid was collected by filtrate and dried in vacuo overnight to give the title product as the tartrate salt of 4-{2-[2-(2(R)-fluoromethyl-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-benzonitrile, mp 156.3° C., MS m/z (M+H)+349; 13C NMR (DMSO) δ 158.6, 154.2, 145.2, 133.2, 132,7, 129.4, 127.7, 122.8, 119.2, 118.9, 111.2, 109.4, 103.0, 85.6 and 84.3, 72.1, 62.8, 53.5, 52.3, 27.2, 26.4, 22.7.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](OCC)=[O:8])=[CH:5][N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[I:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: CCOC(=O)c1cn(C(C)C)nc1I
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)n1cc(CO)c(I)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A solution of ethyl 3-iodo-1-isopropyl-1H-pyrazole-4-carboxylate (740 mg, 2.40 mmol) in tetrahydrofuran (20 mL) was cooled to −78° C. and treated with diisobutylaluminum hydride (1.5 M in toluene, 0.8 mL, 7.21 mmol), dropwise. The mixture was stirred at −78° C. for 1 hour and then warmed to room temperature for 2 hours. The mixture was quenched with 10 mL ethyl acetate, stirred 15 minutes, and then treated with 25 mL saturated aqueous Rochelle's salts. After stirring an additional 1 hour at room temperature, the mixture was diluted with 50 mL ethyl acetate and washed with 100 mL water. The aqueous layer was extracted with an additional 50 mL ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified by flash chromatography (12-100% ethyl acetate/heptanes, 25 g silica gel) to yield 630 mg of (3-iodo-1-isopropyl-1H-pyrazol-4-yl)methanol as a clear oil. +APCI (M+H) 266.8; 1H NMR (400 MHz, CDCl3, δ): 7.37 (s, 1H), 4.49 (m, 3H), 1.67 (t, J=5.9 Hz, 1H), 1.50 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]([O:15]CC)=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].OS([O-])(=O)=O.[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]ccc1-c1ccc(Cl)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1[nH]ccc1-c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
To a solution of ethyl 3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate [see step 2 ACI-02] (8 g, 32.0 mmol) in DMSO (30 mL) was added NaOH (2.56 g, 64.1 mmol) and the reaction mixture was stirred at 70° C. for 20 h. An additional portion of NaOH (0.5 g, 12.5 mmol) was added and stirring at 70° C. was continued for 30 min. The reaction mixture was cooled in an ice bath and acidified with aqueous 1M KHSO4 (80 mL). The solid was filtered off and washed with aqueous 1M KHSO4 (20 mL), H2O (3×25 mL) and heptane (3×25 mL) and dried on air. The residue was dissolved in EtOAc (600 mL), dried (Na2SO4) and the solvent was removed in vacuo. The product was stirred in i-Pr2O/heptane (1:1, 100 mL). The solid was filtered and off dried in vacuo to give the desired product as a a white solid (6.04 g, 85%).
Reaction SMILES: NC1C=C2NC(C3C=C(N[C:19](C4OC(F)=CC=4)=[O:20])C=CC=3Cl)=NC2=NC=1.C(Cl)(=O)OC(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:42]([C:44]2[O:45][C:46](F)=[CH:47][CH:48]=2)=[O:43])=[CH:37][C:36]=1[C:50]1[N:51](C(OC(C)C)=O)[C:52]2[C:53]([N:65]=1)=[N:54][CH:55]=[C:56]([NH:58][C:59]([O:61][CH:62]([CH3:64])[CH3:63])=[O:60])[CH:57]=2.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1>[CH:62]([O:61][C:59](=[O:60])[NH:58][C:56]1[CH:57]=[C:52]2[NH:51][C:50]([C:36]3[CH:37]=[C:38]([NH:41][C:42]([C:44]4[O:45][C:46]([O:20][CH3:19])=[CH:47][CH:48]=4)=[O:43])[CH:39]=[CH:40][C:35]=3[Cl:34])=[N:65][C:53]2=[N:54][CH:55]=1)([CH3:64])[CH3:63]
Reactant: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)n(C(=O)OC(C)C)c2c1
Reactant: Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)[nH]c2c1
Agent: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(-c3nc4ncc(NC(=O)OC(C)C)cc4[nH]3)c2)o1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 20 mL vial was transferred N-(3-(6-amino-1H-imidazo[4,5-b]pyridin-2-yl)-4-chlorophenyl)-5-fluorofuran-2-carboxamide (1-9) (60 mg, 0.161 mmol) in pyridine (2 mL), and the isopropyl carbonochloridate (1M solution, 0.241 mmols, 1.5 eq) was added. The brown reaction mixture was stirred at room temperature for 12 hrs. Checked via LCMS for the desired peak and found M+H (544) which seemed to be isopropyl 2-(2-chloro-5-(5-fluorofuran-2-carboxamido)phenyl)-6-((isopropoxycarbonyl)amino)-1H-imidazo[4,5-b]pyridine-1-carboxylate. Removed all solvents under vacuo and the reaction mixture was redissolved in MeOH (2 mL), and added potassium carbonate (55 mg, 0.402 mmols, 2.5 eq). The reaction mixture was heated at 60 C for 1 hr, checked via LCMS once more and found the M+H=470 as the only peak. The reaction mixture was filtered and the methanolic solution was then injected into the mass triggered HPLC to isolate the desired compound, treated with carbonate based resin and isolated the free base of Compound 39.