Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.[O:29]1[CH2:32][C:31](=O)[CH2:30]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH:31]5[CH2:32][O:29][CH2:30]5)[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=C1COC1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C5COC5)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
To a suspension of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62, 78.4 mg, 0.181 mmol) in dry MeOH (1.0 mL) was sequentially added 3-oxetanone (39.2 mg, 0.544 mmol) and acetic acid (0.30 mL). The mixture was stirred at ambient temperature for 5 minutes and sodium cyanoborohydride (72.0 mg, 1.29 mmol) was added slowly in portions over 5 minutes. The mixture was stirred at ambient temperature for 16 hours and additional 3-oxetanone (2.0 equivalents) was added. Stirring was continued for 4 hours and the mixture concentrated to dryness. The residual solids were partitioned into DCM and 1M K2CO3 (3 mL each) and 1M NaOH was added to adjust the pH to 13. The mixture was stirred until both layers were homogeneous, the DCM layer was removed and the aqueous layer was extracted with DCM. The DCM extracts were combined and dried over Na2SO4. The solution was eluted through a silica gel plug eluting with DCM, 10% MeOH/EtOAc, and then 20% (9:1 MeOH/NH4OH)/EtOAc. The 20% pool was concentrated to give a colorless glass. The glass was dissolved in minimal DCM and treated with hexanes to give a granular white precipitate. The suspension was concentrated to afford the title compound (54 mg, 72% yield) as a white solid. MS (apci) m/z=416.2 (M+H).
Reaction SMILES: [C:1]1([CH:7]2[N:12]([C:13]3[O:14][C:15]4[C:16](=[C:18]([C:22]([OH:24])=O)[CH:19]=[CH:20][CH:21]=4)[N:17]=3)[CH2:11][CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:27][C@H:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:29][CH:28]([NH:27][C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:15]4[O:14][C:13]([N:12]5[CH2:11][CH2:10][O:9][CH2:8][C@@H:7]5[C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:17][C:16]=34)=[O:24])[CH:33]([CH2:34][CH2:35]1)[CH2:32][CH2:31]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cccc2oc(N3CCOCC3c3ccccc3)nc12
Agent: Cl
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(N3CCOC[C@@H]3c3ccccc3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-(3-phenylmorpholino)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-(3-phenylmorpholino)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][NH:18][CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[CH:21][C:20]1=2.I[CH2:45][CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][N:18]([CH2:45][CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1)[CH:19]1[CH2:28][CH2:27][CH2:26][C:25]2[N:24]=[C:23]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:22]=[CH:21][C:20]1=2
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: COC(=O)c1ccc(CCI)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of 69 g (111.24 mmol) of ethyl 5-{[2-(2-{[3-chloro-4′-(trifluoromethyl)biphenyl-4-yl]methoxy}-phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 86A), 129 g (444.98 mmol) of methyl 4-(2-iodoethyl)benzoate and 17.68 g (166.87 mmol) of anhydrous sodium carbonate in 1500 ml of dry acetonitrile was stirred at a bath temperature of 110° C. overnight. A further 65.54 g of methyl 4-(2-iodoethyl)benzoate and 23.06 g (166.87 mmol) of powdered potassium carbonate were then added, and the mixture was heated under reflux for another 48 h. After cooling of the reaction mixture, the inorganic salts were filtered off and the filtrate obtained was evaporated to dryness. The resulting residue was taken up in ethyl acetate, washed twice with 10% strength aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then once more evaporated to dryness. The residue obtained was purified chromatographically on silica gel (3 kg) (mobile phase: petroleum ether/ethyl acetate 8:2→7:3). This gave 42 g (54.45 mmol, 49% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.N>CN(C)C=O.O>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:23])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2c(C(N)=O)ncn2-c2cccc(Br)c2C1=O
Reaction time: 0.5 h
Yield: 87 %

Procedure:
24.9 g (74.1 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid were suspended in 100 ml of N,N-dimethylformamide, treated at room temperature with 14.3 g (89 mmol) of 1,1'-carbonyldiimidazole and stirred at 70° for 30 minutes. 50 ml of 25% ammonia were added dropwise at 25°-30°. The reaction mixture was diluted with 200 ml of water and cooled to 0°, and the crystallizate was filtered off under suction and dried. There were obtained 21.6 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of m.p. 278°-279°.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14]Br)[C:9]([CH2:12]Br)=[CH:10][CH:11]=1.[C-:16]#[N:17].O>CS(C)=O>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:1]#[N:2])=[C:8]([CH2:14][C:16]#[N:17])[CH:7]=1
Reactant: COc1ccc(CBr)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CC#N)c(CC#N)c1
Reaction time: 0.25 h

Procedure:
Finely ground sodium cyanide (73 gm., 1.48 m) was suspended in dimethylsulfoxide (500 ml.) by means of a "Vibro-Mixer". A solution of 4-Methoxy-α,α'-dibromo-o-xylene (113 gm., 0.384 m) in dimethylsulfoxide (200 ml.) was added dropwise to the cyanide suspension. The internal temperature was kept at 35°-38° C. by means of an ice bath. The addition took 15 minutes. Agitation of the reaction was continued for a further 11/2 hours. The reaction mixture was poured into water (4 l.). The aqueous mixture was extracted with ether (2×1 l., 3×500 ml.) and the combined ether extracts were washed with dilute hydrochloric acid (6 N) (2×500 ml.), saturated sodium carbonate solution (1×500 ml.), water (3×500 ml.) and saturated sodium chloride solution (2×500 ml.). The ether layer was dried over magnesium sulfate. The dried ethereal solution was evaporated to an oil which was distilled and the fraction with boiling range 160°- 165° (0.1 mm) was collected. wt.=53 gm. The oil obtained was crystallized from ether (650 ml.) to give 45 gm. (m.p. 51°-53°). A second drop of 5.8 gm.(m.p. 49°-51°) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[OH:10])[C:5]#[N:6].Cl[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:11])[C:9]=1[O:10][CH2:17][CH2:16][CH2:15][C:14]#[CH:13])[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)c(O)c(Cl)c1
Reactant: C#CCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: C#CCCCOc1c(Cl)cc(C#N)cc1Cl
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 10.0 g 3,5-dichloro-4-hydroxybenzonitrile, 6.2 mls 5-chloro-1-pentyne, 18.38 g milled potassium carbonate (100%) and 0.88 g potassium iodide in 125 mls N-methylpyrrolidone was heated at 60° C. with stirring overnight. An additional 4.6 g milled potassium carbonate and 2.82 mls 5-chloro-1-pentyne was added and heating was continued for two days. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were washed with aqueous 10% potassium bisulfate solution, water and saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. The resulting oily residue was subjected to flash chromatography (silica gel; 10:90 ethyl acetate/hexane) to yield 7.03 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25]3)=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.[OH-].[K+].C1COCC1.Cl>C(O)C.O>[CH3:28][C:22]1([CH3:29])[C:21]2[C:26](=[CH:27][C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=3)=[CH:19][CH:20]=2)[O:25][CH2:24][CH2:23]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)OCCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)OCCC2(C)C
Temperature: 45 °C
Yield: 79.4 %

Procedure:
A solution of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid methyl ester (0.474 g, 1.15 mmole) in 8 mL of ethanol was treated with a solution of potassium hydroxide (1.3 g) in 5 mL of water. THF (4 mL) was added and the mixture was heated at 45° C. for two hours, diluted with 20 mL of water and the pH was adjusted to 2 with concentrated HCl. The mixture was then extracted with three 20 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow foam. The product was purified by recrystallization from acetonitrile/water to yield 0.362 g of 4-[2-(4,4-dimethyl-chroman-7-yl)-heptyloxy]-benzoic acid (1) as a white solid. M.p.: 91.5-93.3° C.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15].[N+:22]([O-])([OH:24])=[O:23]>>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([N+:22]([O-:24])=[O:23])[C:13]=1[CH:14]=[O:15]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C=O)c1O
Agent: O=S(=O)(O)c1ccccc1
Product: COc1ccc([N+](=O)[O-])c(C=O)c1O
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-3-methoxybenzaldehyde benzenesulfonate (200 g, 0.685 mole) was added to 90% nitric acid (400 mL) with the temperature maintained at 0° ±2° over a period of one-half to one hour. The reaction mixture was stirred an additional 0.5 hour and poured over ice (2.5 L) with stirring. After standing several hours, the solid was collected by filtration and washed with water (500 mL). The solid was then suspended in acetone (1.25 L) and the mixture was heated to reflux for 0.5 hour, concentrated to 500 mL and cooled to 15° C. The resultant solid was collected by filtration and washed with cold acetone (125 mL) to provide the title compound, 138.5 g (60%), mp 151°-155° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4I)(=[O:21])=[O:20])[CH2:15][CH2:14]3)[C:10]2=[O:29])=[CH:5][CH:4]=1)[CH3:2].[NH:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35].C([O-])([O-])=O.[K+].[K+].CNCCNC>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][N:16]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[C:10]2=[O:29])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCCN1
Reactant: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4I)CC3)C2=O)cc1
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4N4CCCC4=O)CC3)C2=O)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-(4-ethyl-phenyl)-8-(2-iodo-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.06 g), compound of example 74), 2-pyrrolidinone (0.015 g), K2CO3 (0.055 g) and N,N′-dimethylethylenediamine (0.015 g) was heated in DMF under an argon atmosphere for 24 h at 150° C. The mixture was then cooled to RT and extracted with AcOEt. The extracts were combined, filtered, washed with water and dried over sodium sulphate. The solvent was removed in vacuo. The residue was chromatographed over silica gel (AcOEt/heptane, gradient from 0 to 50%, then MeOH/CH2Cl2 from 0 to 7%) to give the desired 2-(4-ethyl-phenyl)-8-[2-(2-oxo-pyrrolidin-1-yl)-benzenesulfonyl]-2,8-diaza-spiro[4.5]decan-1-one as a yellow oil. MS (ESI): 482.21 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-])=O)(=[O:11])=[O:10])[C:5](O)=[O:6].CCO.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.[Pd]>[CH2:3]([CH:4]1[C:5](=[O:6])[NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:9](=[O:11])(=[O:10])[NH:8]1)[CH:2]([CH3:21])[CH3:1]
Reactant: CC(C)CC(NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CC1NS(=O)(=O)c2ccccc2NC1=O
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A stirred suspension of N-(3′-methyl-1′-carboxybutyl)-2-nitrobenzenesulfonamide (6.7 g; 21.2 mmol) and 10% Pd/C (200 mg) in abs. EtOH was hydrogenated at 1 bar. The reaction mixture was filtered through celite and evaporated to dryness. A solution of the crude product in dry THF (50 ml) at 0° C. was added N-hydroxysuccinimide (2.53 g; 22 mmol) and DCC (4.54 g; 22 mmol). The reaction mixture was slowly warmed to rt. and left with stirring over night. The reaction mixture was filtered and the solid material was washed with THF. The combined organic fractions were evaporated to dryness and the remanense added H2O and extracted with EtOAc. The combined organic fractions were dried (Na2SO4) and evaporated to dryness to give 3 g (53%) product.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]2[C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64]([O:68][C:69]([N:71]1[CH:76]2[CH2:77][CH2:78][CH:72]1[CH2:73][NH:74][CH2:75]2)=[O:70])([CH3:67])([CH3:66])[CH3:65]>CN(C=O)C>[C:64]([O:68][C:69]([N:71]1[CH:72]2[CH2:78][CH2:77][CH:76]1[CH2:75][N:74]([C:21]([C:20]1[CH:19]=[N:18][C:17]([NH:16][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[N:7]([CH:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:25][CH:24]=1)=[O:22])[CH2:73]2)=[O:70])([CH3:67])([CH3:65])[CH3:66]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a 1 mL DMF solution of 6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (50 mg, 0.122 mmol) was added DIPEA (32 mg, 0.043 mmol) and HBTU (49 mg, 0.129 mmol). After stirring for 15 m at room temperature 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (31.2 mg, 0.147 mmol) was added and the reaction mixture was left to stir at room temperature for 4 h. The reaction was quenched by pouring into brine and extracted with EtOAc. The organic extracts were dried with Na2SO4, filtered and concentrated. The crude product was purified by NP-LC (Analogix, 10% MeOH in EtOAc) to yield 3-[6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol). MS m/z 603.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Cl:20][CH2:21][C:22]([NH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: O=C(Cl)CCl
Reactant: NCCc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCl)NCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a solution of 4-fluorophenylethylamine (1.0 equivalent) in dried THF was added Hunig's base (DIEA) (1 equivalent). The mixture was then stirred for 3 minutes at 0° C. Thereafter, a solution of chloroacetylchloride (1.0 equivalent) in THF was added via a syringe over a period of 7 minutes. The reaction mixture was then stirred at room temperature for 1 hour after which time the reaction mixture was condensed in vacuo, quenched with water, extracted with ethyl acetate (3×) and dried over Na2SO4. After concentration in vacuo, compound 1 shown above was obtained, which was carried on further without further purification. LC/MS=M+H 216.1 at 2.18 minutes.
Reaction SMILES: Cl[C:2]1[C:11](C(C(=CN(C)C)C(OCC)=O)=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6](Cl)=[C:7](F)[CH:8]=2)[N:3]=1.C1([NH2:29])CC1>ClC(Cl)Cl>[CH2:10]1[CH2:11][CH2:2][N:3]2[C:7](=[N:29][CH2:6][CH2:5][CH2:4]2)[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: NC1CC1
Solvent: ClC(Cl)Cl
Product: C1CCC2=NCCCN2CC1
Yield: 122.8 %

Procedure:
A solution of 20.6 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 6 g of cyclopropylamine in 100 cm3 of trichloromethane is stirred at a temperature close to 20° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. The residue is taken up in 180 cm3 of ethanol and 10 g of DBU and the solution obtained is heated at a temperature close to 78° C. for 4 hours. After cooling to a temperature close to 20° C., the precipitate obtained is drained and washed with twice 60 cm3 of ethanol. 13.65 g of 8-chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a pale yellow solid melting at 256° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9](Cl)(Cl)Cl)[CH:8]=1>>[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH:8]=1)[C:9]#[N:1]
Reactant: N
Reactant: Fc1cccc(C(Cl)(Cl)Cl)c1
Product: N#Cc1cccc(F)c1

Procedure:
The concentration of the aqueous ammonia is preferably from 25 to 40%. It is used usually in an amount of from 10 to 40 moles, preferably from 20 to 30 moles, per mole of the 5-fluorobenzotrichloride. The reaction temperature is preferably from 90° to 120° C., and the reaction time is preferably form 5 to 20 hours. After completion of the reaction, the ammonia is recovered, and then the mixture is filtered. The filtrate is distilled to obtain the desired 5-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[NH:10]1.[H-].[Na+].[CH3:31]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[N:10]1[CH3:31]
Reactant: CCN(CC)c1cccc2nc3n(c12)CCC(=O)NC3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)N(C)C3c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-(2,4-dichlorophenyl)-7-(diethylamino)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,2-a]benzimidazol-3-one (83.5 mg, 0.200 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 20.0 mg, 0.500 mmol) at room temperature. After 15 min, methyl iodide (62.3 μL, 1.00 mmol) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture and by preparative NH TLC eluting with a 33% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (5.0 mg, 0.0115 mmol, 5.7%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][C:5]=1[CH3:14])#[N:2].[F:15][C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=1[C:18](=[O:21])[CH2:19][Cl:20]>C(#N)C>[ClH:20].[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH:19]([CH2:19][C:18]([C:17]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:16]=3[F:15])=[O:21])[C:18]([C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:16]=3)=[O:21])[CH:9]=[C:10]([F:13])[CH:11]=2)=[N:6][C:5]=1[CH3:14])#[N:2]
Reactant: Cc1[nH]c2ncc(F)cc2c1CC#N
Reactant: O=C(CCl)c1ccc(F)cc1F
Solvent: CC#N
Product: Cc1nc2n(C(CC(=O)c3ccc(F)cc3F)C(=O)c3ccccc3)cc(F)cc-2c1CC#N
Product: Cl

Procedure:
The title compound was prepared from 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine (10 mg, 0.053 mmol) and 2,4-difluorophenacyl chloride (128 mg, 0.67 mmol) in acetonitrile (0.2 ml) in the same fashion as described in example 71; yield 16 mg (80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[C:5]2[CH:12]1[CH2:15][CH2:14][CH2:13]1.C(OC([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C>>[CH2:29]([C@@H:24]1[NH:23][CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[N:6]=[C:5]3[CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:25]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cn1nc(C2CCC2)c2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cc1ccccc1
Product: Cn1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Yield: 99 %

Procedure:
The title compound was prepared by the method outlined for Example 1 using 5-Bromo-3-cyclobutyl-1-methyl-1H-indazole as the aryl halide and (S)-2-benzyl-piperazine-1-carboxylic acid tert-butyl ester as the amine component to afford the title compound as a brown oil (409 mg, 99%). 1H NMR (MeOH-d4) 8.72 (d, J=8.7 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.32-7.18 (m, 6H), 4.08 (s, 3H), 3.79-3.46 (m, 3H), 3.35-3.34 (m, 1H), 3.31-3.30 (m, 2H), 3.15-3.07 (m, 4H), 2.88-2.77 (m, 5H), 2.69-2.61 (m, 1H). LC/MS (Method B) 2.49 min, [M+1]+ 361.