Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][CH:38]([C:45]2([CH3:50])[CH2:49][CH2:48][CH2:47][CH2:46]2)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]([F:51])=[CH:33][C:32]=1[C:52]#[N:53].ClC1N=C(N[C@@H](C2(C)CCCC2)CC(OCC)=O)C(F)=CC=1C#N.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.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]>[C:52]([C:32]1[CH:33]=[C:34]([F:51])[C:35]([NH:37][C@@H:38]([C:45]2([CH3:50])[CH2:46][CH2:47][CH2:48][CH2:49]2)[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:36][C:31]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:8]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:9]=1)#[N:53]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CCOC(=O)CC(Nc1nc(Cl)c(C#N)cc1F)C1(C)CCCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CCOC(=O)C[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(C)CCCC1
Solvent: O
Product: CCOC(=O)C[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)c(C#N)cc1F)C1(C)CCCC1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.155 g, 0.373 mmol), racemic ethyl 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-3-(1-methylcyclopentyl)propanoate, 143a, (0.120 g, 0.339 mmol) and K3PO4 (0.288 g, 1.357 mmol) in 2-methyl THF (10.0 mL) and H2O (0.24 mL) was degassed under a stream of nitrogen for 30 minutes. To the mixture was added X-phos (0.020 g, 0.041 mmol) and Pd2(dba)3 (0.008 g, 0.008 mmol). The reaction mixture was stirred at 130° C. in a pressure tube for 45 minutes. The organic phase was filtered through a pad of celite and concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (30% EtOAc/Hexanes) to afford 150 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.44 (dt, J=15.3, 7.7 Hz, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.13 (t, J=7.6 Hz, 2H), 7.41 (d, J=10.3 Hz, 1H), 7.32 (d, J=7.5 Hz, 2H), 5.38 (t, J=9.7 Hz, 1H), 4.89 (td, J=10.1, 3.3 Hz, 1H), 4.02-3.91 (m, 2H), 2.74 (dd, J=15.1, 3.5 Hz, 1H), 2.52 (dd, J=15.1, 10.2 Hz, 1H), 2.40 (s, 3H), 1.61 (ddt, J=32.0, 20.7, 7.7 Hz, 7H), 1.49-1.30 (m, 3H), 1.27 (t, J=7.1 Hz, 3H), 1.08-0.97 (m, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=4.22 min (M+H) 608.29.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Br:24][C:25]1[CH:26]=[C:27]([C:32]([OH:34])=O)[NH:28][C:29]=1[CH2:30][CH3:31].Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:44]=[C:45]([CH:49]=[C:50]([Cl:52])[N:51]=2)[C:46]([NH2:48])=[O:47])[CH2:39][CH2:38]1>CN(C=O)C>[Br:24][C:25]1[CH:26]=[C:27]([C:32]([NH:36][CH:37]2[CH2:38][CH2:39][N:40]([C:43]3[CH:44]=[C:45]([CH:49]=[C:50]([Cl:52])[N:51]=3)[C:46]([NH2:48])=[O:47])[CH2:41][CH2:42]2)=[O:34])[NH:28][C:29]=1[CH2:30][CH3:31]
Reactant: CCc1[nH]c(C(=O)O)cc1Br
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Br
Reaction time: 8 h

Procedure:
Diisopropylethylamine (0.28 ml, 1.64 mmol), EDC (0.088 g, 0.46 mmol) and HOAT (0.063 g, 0.46 mmol) were added to a stirred solution of 4-bromo-5-ethyl-1H-pyrrole-2-carboxylic acid (Intermediate 10, 0.1 g, 0.46 mmol) in DMF (1.5 ml) at room temperature. The resultant solution was stirred for 30 mins and a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.14 g, 0.55 mmol) in 3 ml of DMF was added. The reaction was stirred overnight, then concentrated under vacuum and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2) and the combined organic extracts were washed with 1 N HCl, water and brine, dried over MgSO4 and concentrated under vacuum. The residue was purified by reverse phase chromatography to give the desired product as a white solid.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[I-].[K+].C([C@H]1N(C(=O)C2C=CC=C(OC)C=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CCCCCBr
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Agent: [I-]
Agent: [K+]
Product: CCCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Yield: 55 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated with 1-bromopentane and potassium iodide (1.2 eq) according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 4) to yield (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-pentyl-3,4-dihydroquinoxalin-2(1H)-one (55%). MS (ESI) m/z 399 ([M+H]+).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:14][S:15]([O:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[C@H:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:4]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C[C@@H]1C[C@@H](CO)NC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H]1C[C@@H](COS(C)(=O)=O)NC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 8.0 g of (3S,5S)-5-hydroxymethyl-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone and 4.95 ml of methanesulphonic acid chloride in 100 ml of methylene chloride, a solution of 9.0 ml of triethylamine in 15 ml of methylene chloride is added dropwise at 0° C. within 15 minutes. The mixture is stirred for one hour at 0° C. and for a further hour at ambient temperature. After the addition of 20 ml of water the organic phase is separated off and washed twice with water. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure in vacuo. The crude product is chromatographed with ethyl acetate/methanol (15:1) over silica gel and the solid obtained is recrystallised from methyl tert.butylether/acetone.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([C:32]#[N:33])[CH:23]=4)=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:35]>O1CCOCC1.C(OCC)C>[ClH:35].[NH2:7][C@@H:8]1[C:16]2[C:11](=[C:12]([C:17]3[S:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([CH:23]=4)[C:32]#[N:33])=[N:20][N:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4NC(=O)OC(C)(C)C)s2)cc1C#N
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
Prepared using General Procedure 5. To a stirred solution of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1.1 g, 2.3 mmol) in 1,4-dioxane (10 mL) was added 4N HCl solution of in 1,4-dioxane (10 mL). The reaction mixture was stirred at 55° C. for 2.5 h. Upon cooling to 0° C., the reaction mixture was diluted with diethyl ether (100 mL) and the resulting solid was filtered and dried to afford 980 mg (96%) of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 as off-white solid. LCMS-ESI (m/z) calculated for C21H20N4OS, 376.1; found 377.1 (M+H). tR=2.35 min. 1H NMR (400 MHz, DMSO) δ 8.64-8.51 (m, 3H), 8.41 (d, J=2.3 Hz, 1H), 8.32 (dd, J=8.9, 2.4 Hz, 1H), 7.99 (d, J=7.4 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.59-7.49 (m, 2H), 4.95 (dt, J=12.2, 6.1 Hz, 1H), 4.84 (s, 1H), 3.54-3.32 (m, 1H), 3.30-3.15 (m, 1H), 2.65-2.53 (m, 1H), 2.12 (ddd, J=13.9, 5.6, 3.0 Hz, 1H), 1.37 (dd, J=10.4, 6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.61, 166.11, 161.5, 143.05, 141.73, 134.16, 133.45, 129.74, 128.26, 127.84, 126.47, 122.33, 115.79, 115.2, 102.53, 72.43, 54.75, 31.48, 30.12, 21.74. Chiral HPLC: (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 was eluted using 30% EtOH in hexanes plus 0.1% DEA: 99.0% ee, tR=34.2 min.
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].[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[N:25]([CH3:32])[C:26](=[O:31])[CH2:27][NH:28][C:29](=[O:30])[C:23]=2[CH:22]=1.Cl.N1C=CC=CC=1>C(OC(O)C)C>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:20][C:21]1[CH:34]=[CH:33][C:24]2[N:25]([CH3:32])[C:26](=[O:31])[CH2:27][NH:28][C:29](=[O:30])[C:23]=2[CH:22]=1)[CH3:14]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: CN1C(=O)CNC(=O)c2cc(N)ccc21
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)C(=O)NCC(=O)N4C)c2cc1OCC
Yield: 99.8 %

Procedure:
A mixture of 0.5 g (1.8 mmol) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 0.35 g (1.8 mmol) of 7-amino-1-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine, and 0.21 g of pyridine hydrochloride was refluxed in ethoxyethanol for 5 hr. The solvent was removed at reduced pressure. The residue was stirred with ammonium hydroxide and the insoluble material was collected to give 0.8 g of title compound as a a tan solid. crystals: mass spectrum (electrospray, m/e): M+H 446.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:16]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[N:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[O:10])=[CH:4][CH:3]=3)[CH2:35][CH2:34]2)=[N:25][N:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Cc1ccc(Cl)nc1)N1CCCC1
Reactant: c1ccc(Cc2nnc(N3CCNCC3)c3ccccc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1)N1CCCC1
Temperature: 90 °C

Procedure:
To a solution of this amide (0.22 g, 1 mmol) and 1-benzyl-4-piperazin-1-yl-phthalazine (0.15 g, 0.5 mmol) in toluene (10 mL) were added (2-biphenyl)dicyclohexyl phosphine (35 mg, 0.1 mmol), Pd(OAc)2 (11 mg, 0.05 mmol) and KOtBu (336 mg, 3 mmol). The mixture was degassed and then heated in a microwave reactor at 90° C. The reaction mixture was cooled to room temperature and filtered. Water was added to the filtrate and extracted with EtOAc. The combined organic layers were washed with water, sat. NaHCO3, brine, dried over Na2SO4, filtered and concentrated.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[NH:14][C:13]2=[O:22])[CH2:8][CH2:7]1)=O)C.[OH-].[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[N:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:13](=[O:22])[NH:14][C:15]=2[CH:20]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(F)ccc32)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=c1[nH]c2cc(F)ccc2n1C1CCNCC1
Temperature: 25 °C
Yield: 73 %

Procedure:
4-(5-Fluoro-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester was refluxed with 10% sodium hydroxide (2 mL) for 4 h. The reaction was allowed to cool to room temperature and acidified with concentrated hydrochloric acid. The acidified reaction mixture was adjusted to pH 10 with the slow addition of sodium carbonate. The pink solid that formed was collected by filtration and vacuum dried to give 5-Fluoro-1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (29.4 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=1.Br[C:21]1[C:22](=[O:29])[N:23]([CH3:28])[CH:24]=[C:25]([Br:27])[CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Br:27][C:25]1[CH:26]=[C:21]([NH:1][C:2]2[N:3]=[CH:4][N:5]([CH:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[CH:6]=2)[C:22](=[O:29])[N:23]([CH3:28])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(N)c2)CC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2cn(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Temperature: 95 °C

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 243c (2.3 g, 8.6 mmol), 3,5-dibromo-1-methyl-pyridin-2(1H)-one (2.3 g, 8.6 mmol), tris-(dibenzylideneacetone)dipalladium(0) (789 mg, 0.86 mmol), XantPhos (994 mg, 1.72 mmol), Cs2CO3 (5.6 g, 17.2 mmol), and 1,4-dioxane (80 mL). After three cycles of vacuum/argon flush, the mixture was heated at 95° C. for 4 hrs. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 20:1) to afford 243d as yellow oil solid (2.3 g, 59%). MS-ESI: [M+H]+ 452.3.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:4][CH2:3][CH2:2]1>CCO.[Rh].[Pt]=O.[Ru]>[CH:1]1([O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OC2CCC2)ccn1
Agent: O=[Pt]
Agent: [Rh]
Agent: [Ru]
Solvent: CCO
Product: C1CC(OC2CCNCC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-cyclobutoxypyridine (13) (3.8 g, 25.47 mmol) and rhodium 5% on alumina (0.38 g, 0.05 mmol) in EtOH (50 mL) were stirred under an atmosphere of hydrogen at 5 bar and 25° C. for 16 hours. GCMS analysis indicated no reaction so the mixture was heated to 60° C. for 5 hours but analysis still only indicated trace product formation. Platinum Oxide (0.2 g) catalyst was added and stirred overnight at 60° C., 5 bar, but still no more product formation. The reaction mixture was transferred to a high pressure autoclave and heated overnight at 80° C. and 50 bar no more product formation was observed, thus temperature increased to 100° C. and pressure to 80 bar and left overnight bar but analysis, once more, indicated no more product formation. Thus added 5% ruthenium on Carbon (0.2 g) and heated overnight at 120° C. and 100 bar. Analysis showed no remaining starting material. The reaction was cooled and filtered and solvent evaporated to afford a yellow oil. The crude product was purified by distillation at 0.55 mBar, collecting fractions that distilled at 55° C. to afford the product as a colourless oil, which was used in next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:7]2[C:8]3[CH:9]=[C:10]([C:15]([NH:17][C:18]4[N:19]=[C:20]([C:24]([OH:26])=O)[N:21]([CH3:23])[CH:22]=4)=[O:16])[CH:11]=[CH:12][C:13]=3[CH:14]=[C:6]2[C:5](=[O:27])[NH:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[C:50]([NH2:54])([CH3:53])([CH3:52])[CH3:51].C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:50]([NH:54][C:24]([C:20]1[N:21]([CH3:23])[CH:22]=[C:18]([NH:17][C:15]([C:10]2[CH:11]=[CH:12][C:13]3[CH:14]=[C:6]4[C:5](=[O:27])[NH:4][CH2:3][C:2]([CH3:28])([CH3:1])[N:7]4[C:8]=3[CH:9]=2)=[O:16])[N:19]=1)=[O:26])([CH3:53])([CH3:52])[CH3:51]
Reactant: Cn1cc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)nc1C(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2ccc3cc4n(c3c2)C(C)(C)CNC4=O)nc1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
To a solution of 4-{[(4,4-dimethyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)carbonyl]amino}-1-methyl-1H-imidazole-2-carboxylic acid (104 mg, 0.27 mmol) in DMF (2 mL) are added N-hydroxybenzotriazole (74 mg, 0.55 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (105 mg, 0.55 mmol). After stifling for 10 min at 50° C., tert-butylamine (0.06 mL, 0.55 mmol), N,N-diisopropylethylamine (0.10 mL, 0.55 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.06 mmol) are added. The reaction mixture is stirred at room temperature for 8 h. The solvent is removed under N2 stream to afford the crude compound which is purified by flash column chromatography to afford the title compound (61 mg, 51%). LCMS (ESMS): m/z 437.78 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:37])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C:11]1[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)[CH2:22][C:21](=[O:37])[NH:20][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCC5)c(C)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (4-methyl-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example M111) (0.33 g, 0.64 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (223 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]O)[CH:7]=1.S(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][Cl:19])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Cl)cc1CCCOCCO
Product: COc1ccc(Cl)cc1CCCOCCCl

Procedure:
11.2 g of 2-[3-(5-chloro-2-methoxyphenyl)propyloxy]-ethanol and 20 ml thionyl chloride are stirred at 50° C. for 3 hours; the excess thionyl chloride is distilled off in vacuo. 11.3 g of 2[3-(5-chloro-2-methoxyphenyl)propyloxy]ethyl chloride are obtained as a brown oil.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:13]=[C:12](Br)[S:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C:7]([C:9]2[CH:13]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[S:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(Br)c1)N1CCCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(c1csc(-c2ccccn2)c1)N1CCCCC1
Yield: 12 %

Procedure:
A mixture of piperidin-1-yl-(5-bromo-thiophen-3-yl)-methanone (76 mg, 1 eq.), tributyl(2-pyridyl)tin (0.102 mL, 1 eq.) and PdCl2(PPh3)2 (0.011 g, 0.1 eq) were heated at 100° C. in toluene (1 mL) for 6 hours. The solvent was evaporated and the residue purified by column chromatography (EtOAc/iso-hexane) to give the desired product (9.2 mg, 12%). LCMS m/z 273 [M+H]+ R.T.=2.73 min (Analytical Method 3).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([I:21])=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([I:21])[C:14]=12
Reactant: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(I)nn2C1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 100.3 %

Procedure:
1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (intermediate N) (13.12 g, 32.7 mmol) was suspended in acetone (240 mL) and the mixture was cooled to 0° C. Added aqueous 5 N HCl (200 mL) dropwise, keeping the temperature less than 4° C. during the addition. After the addition was complete the mixture was allowed to come to ambient temperature and stirred for 18 hours. The remaining solid was removed by filtration, and the filtrate was neutralized with saturated aqueous sodium bicarbonate. The precipitate was collected by filtration and washed with water and dried in vacuo to give 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-cyclohexanone (8.20 g, 32.8 mmol): 1H NMR (DMSO-d6, 400 MHz) 8.23 (s, 1H), 5.18 (m, 1H), 2.64-2.73 (m, 2H), 2.26-2.37(m, 4H), 2.17-2.30 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[C:26]([C:29]([NH2:31])=[O:30])[O:27][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd].[Pd].[Pd].O1CCOCC1>[CH:12]1([NH:11][C:5]2[C:6]3[N:7]([N:8]=[CH:9][N:10]=3)[C:2]([C:24]3[CH:25]=[C:26]([C:29]([NH2:31])=[O:30])[O:27][CH:28]=3)=[CH:3][N:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2coc(C(N)=O)c2)OC1(C)C
Reactant: Brc1cnc(NC2CCC2)c2ncnn12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1cc(-c2cnc(NC3CCC3)c3ncnn23)co1
Temperature: 90 °C
Yield: 91.1 %

Procedure:
The product of Step 1 (900 mg, 3.35 mmol), Intermediate 5 (4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-furan-2-carboxylic acid amide, 1.8 g, 4.02 mmol), tetrakis palladium triphenylphosphine (970 mg, 0.84 mmol), sodium carbonate solution (1.5 M, 18 mL, 26.8 mmol) and dioxane (20 mL) are combined in a flask. The mixture is degassed with nitrogen for 10 min then sealed and heated at 90° C. for 18 h. The reaction mixture is cooled and the precipitate collected by filtration. The precipitate is washed with 2% methanol: dichloromethane (2 mL) to give the title compound as a white solid (910 mg, 91%). 1H-NMR (400 MHz, d6-DMSO)=1.74-1.76 (m, 2H), 2.22-2.26 (m, 2H), 2.32 (brs, 2H), 4.70 (brd, 1H, J=7.6), 7.58 (s, 1H), 7.86 (s, 1H), 7.97 (s, 1H), 8.12 (s, 1H), 8.35 (d, 1H, J=7.2), 8.69 (d, 1H, J=9.6). LCMS: Rt 2.63 min (90.4%), m/z (APCI) 299 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[N:32]1[C:36]([CH3:37])=[N:35][CH:34]=[N:33]1)[C:26](O)=[O:27]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([C:18]([F:20])([F:19])[F:21])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([N:32]3[C:36]([CH3:37])=[N:35][CH:34]=[N:33]3)=[C:23]([F:22])[CH:24]=2)[CH2:2][CH2:3]1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cc1F

Procedure:
The title compound is prepared from cyclopropyl-(3′-fluoro-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=4.64 min; Mass spectrum (ESI+): m/z=507 [M+H]+.