Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]12[N:37]([C:38](=[O:40])[CH3:39])[CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>>[C:38]([N:37]1[CH:34]2[CH2:35][CH2:36][CH:30]1[CH2:31][N:32]([C:20]([C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25]([N:26]([CH3:27])[CH3:28])=[O:29])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[N:17][CH:18]=1)=[O:22])[CH2:33]2)(=[O:40])[CH3:39]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(=O)N1C2CCC1CNC2
Product: CC(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C2
Yield: 62 %

Procedure:
The 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 1-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanone following amide formation method 3 which gave 2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (43 mg, 62% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.80 (s, 1H) 8.53 (d, J=8.59 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 7.86 (dd, J=8.59, 2.02 Hz, 1H) 6.65 (s, 1H) 4.80-4.73 (m, 1H) 4.73-4.25 (m, 3H) 3.86-3.41 (m, 2H) 3.16 (s, 7H) 2.64-2.42 (m, 2H) 2.23-1.99 (m, 8H) 1.91 (br. s., 2H) 1.83-1.61 (m, 3H); HR-MS (m/z MH+) 531.28 RT 4.27 min
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1

Procedure:
To a solution of 1-BOC-piperazine (3.26 g) and triethylamine (2.68 mL) in dry chloroform (25 mL) was added 3-chloropropanesulfonyl chloride (2.62 g) at 0° C. After 2 h wash with water, dry (Na2SO4), filter and concentrate to give crude material. Product was isolated by flash chromatography (95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@@H:8]([C:19](=[O:24])N(OC)C)[CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])([CH3:4])([CH3:3])[CH3:2].[C:26]([NH:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[CH3:39])([CH3:29])([CH3:28])[CH3:27]>>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[CH:12][C:11]=1[F:18])[C:19](=[O:24])[CH2:39][C:33]1[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=1[C:31](=[O:40])[NH:30][C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(Cl)ccc1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)c1ccc(Cl)cc1CC(=O)[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-1-(methoxy-methyl-carbamoyl)-2-(2,4,5-trifluoro-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.4 g, 3.4 mmol) and N-tert-butyl-4-chloro-2-methyl-benzamide (2.3 g, 10 mmol) followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[N:31]=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[N:31]=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: CC(=O)Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)Nc1nc(N[C@@H](C)c2nc3ccc(F)cc3n2-c2ccccc2)c2nc[nH]c2n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.22 g, 0.68 mmol), N-(6-chloro-9H-purin-2-yl)acetamide (0.20 g, 0.95 mmol) and DIPEA (0.60 mL, 3.38 mmol) in IPA (2 mL) was stirred at 85° C. in a sealed tube for 16 h. The resulting mixture was diluted with DCM/methanol then concentrated in vacuo onto silica gel and this residue was purified by chromatography (SiO2, 0-15% (2M ammonia in methanol) in DCM), and then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 262 as a white solid (0.067 g, 23%). LCMS (method K): Rt 3.14 min, [M+H]+ 431. 1H NMR (DMSO-d6): δ 13.20-12.50 (1H, bs), 9.60 (1H, s), 8.00 (1H, s), 7.71 (1H, m), 7.60 (2H, s), 7.51-7.49 (3H, m), 7.11-7.08 (1H, m), 6.86 (1H, m), 5.64 (1H, m), 2.10 (3H, s), 1.50 (3H, d, J=6.81 Hz)
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCOCCn1c(CCCC)nc2cnc3ccccc3c21
Reactant: Ic1ccccc1
Product: CCCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
Using the general method of Example 12 Part A, 2-butyl-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (4.0 g, 13.08 mmol) was reacted with iodobenzene (1.6 mL, 14.38 mmol) at 90° C. After 15 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil was purified by chromatography over silica gel (98/2 dichloromethane/methanol) and recrystallization from mixture of ethyl acetate/hexane to provide 3.1 g of 2-butyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH:5]([OH:9])[CH2:6][CH:7]=[CH2:8])[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:13][CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][CH:14]([O:18][CH2:19][CH3:20])[CH2:13][O:9][CH:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)[CH2:6][CH:7]=[CH2:8])[CH3:17]
Reactant: C=CCC(O)C1(C)CC1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(OCC(OCC)OCC)C1(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1-(1-methylcyclopropyl)but-3-en-1-ol (C52) (6.0 g, 47.6 mmol) in tetrahydrofuran (50 mL) was added to a 0° C. suspension of sodium hydride (60% in mineral oil, 7.7 g, 190.5 mmol) in tetrahydrofuran (200 mL). After stirring at room temperature for 10 minutes, 2-bromo-1,1-diethoxyethane (97%, 37.5 g, 190.5 mmol) was added drop-wise at room temperature. The reaction mixture was heated to 75° C. for 24 hours. It was then cooled to 0° C., slowly quenched with water (200 mL) and extracted with dichloromethane (3×500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in petroleum ether) afforded the product as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[NH:13][C:14]([CH:17]=O)=[C:15]([CH3:16])[C:8]=2[C:7]1=[O:19])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:17]\[C:14]1[NH:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][N:3]([CH2:20][CH3:21])[CH2:1][CH3:2])[C:7](=[O:19])[C:8]=2[C:15]=1[CH3:16]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCCc2[nH]c(/C=C3\C(=O)Nc4ccc(Cl)cc43)c(C)c2C1=O
Yield: 60 %

Procedure:
The title compound was prepared under the same conditions as described in step 10 of Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j obtained from step 9 of Example 1 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 2 (27 mg, yield 60.0%) as a nacarat solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[C:19]([NH:23][S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29](Br)[CH:28]=1)(=[O:26])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:29]1[CH:28]=[C:27]([S:24]([NH:23][C:19]([CH3:21])([CH3:20])[CH3:22])(=[O:25])=[O:26])[CH:32]=[CH:31][C:30]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-tert-butyl 3-bromo-4-methylbenzenesulfonamide (Combiblocks), the title compound was obtained as an orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [N:1]([C@:4]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:36])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1)=[C:2]=[O:3].CN(C)CCNC(=O)N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1.[CH3:90][C:91]([N:95]1[CH2:100][CH2:99][O:98][CH2:97][CH2:96]1)([CH3:94])[CH2:92][NH2:93]>>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:36])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:4]1([NH:1][C:2]([NH:93][CH2:92][C:91]([CH3:90])([N:95]1[CH2:96][CH2:97][O:98][CH2:99][CH2:100]1)[CH3:94])=[O:3])[CH2:21][CH2:20]2
Reactant: CC(C)(CN)N1CCOCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N=C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)NCC(C)(C)N3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 20 %

Procedure:
The title compound was prepared in 20% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-isocyanato-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(2-(dimethylamino)ethyl)ureido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-methyl-2-morpholinopropan-1-amine was used instead of N,N-dimethylethylenediamine in Step 1. LCMS: m/e 714.3 (M+H)+, 3.95 min (method 8). 1H NMR (500 MHz, MeOD) δ ppm 7.9 (2H, d, J=8.2 Hz), 7.2 (2H, d, J=8.2 Hz), 5.3 (1H, d, J=6.1 Hz), 4.8 (1H, s), 4.7 (1H, s), 4.1 (2H, d, J=12.2 Hz), 3.7-3.9 (2H, m), 3.5-3.6 (2H, m), 3.4-3.5 (2H, m), 3.2 (2H, t, J=11.9 Hz), 2.6-2.7 (2H, m), 2.4 (1H, dd, J=12.1, 8.4 Hz), 2.2 (1H, dd, J=17.1, 6.1 Hz), 2.0 (1H, t, J=10.8 Hz), 1.8-1.9 (1H, m), 1.8 (1H, br. s.), 1.7 (3H, s), 1.7 (1H, td, J=13.3, 3.4 Hz), 1.6-1.6 (2H, m), 1.5-1.6 (4H, m), 1.4-1.5 (3H, m), 1.4-1.4 (6H, m), 1.3 (1H, d, J=9.5 Hz), 1.1 (3H, s), 1.1 (3H, br. s.), 1.1 (3H, br. s.), 1.0 (3H, s), 1.0 (3H, s).
Reaction SMILES: [CH:1](NC(C)C)(C)C.CCCCCC.C([Li])CCC.[CH3:19][C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[CH:22][CH:21]=1.CI.[Cl-].[NH4+]>C1COCC1>[CH2:19]([C:20]1[C:25]([C:26]#[N:27])=[CH:24][N:23]=[CH:22][CH:21]=1)[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: Cc1ccncc1C#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccncc1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (9.1 ml) in THF (50 ml) was cooled to −30° C. and an n-butyllithium hexane solution (1.61 M, 37 ml) was added. The mixture was stirred for 30 min. After cooling the reaction mixture to −78° C., a solution of 4-methylnicotinonitrile (7.01 g) in THF (50 ml) was added dropwise and the mixture was stirred for 15 min. Methyl iodide (9.1 ml) was added and the mixture was heated to −40° C., and saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) for purification to give the title compound (6.67 g) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH3:17]COCC.[Li]C.Cl>C1COCC1.CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:17])[CH2:9][CH2:10][CH2:11][NH:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Fc1cccc(C2=NCCC2)c1
Agent: Cl
Agent: FB(F)F
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2cccc(F)c2)CCCN1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (6.1 g, 37.4 mmol) in 100 mL THF was cooled to −78° C., and boron trifluoride diethyl etherate (9.47 mL, 74.8 mmol) was added drop-wise over 5 minutes. The resulting cloudy reaction mixture was stirred at −78° C. for 40 minutes. MeLi (1.6 M in diethyl ether, 46.7 mL, 74.8 mmol) was added drop-wise over 10 minutes. The mixture was stirred at −78° C. for another 2 hours, then warmed up to ambient temperature overnight. For workup, water and EtOAc were added to the reaction mixture, and the aqueous layer was acidified with HCl solution. After separating and discarding the organic layer, the aqueous layer was basified with NaOH (6 N, aq.) to pH=12 and extracted twice with EtOAc. The combined organic extracts was dried over Na2SO4 and concentrated to get a mixture of the desired product (2-(3-fluorophenyl)-2-methylpyrrolidine) and starting material (4.3 g, 1.3:1 of the desired product:starting material, 37% yield). The crude product was used in the next step without any further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5](I)[C:3]=1[NH2:4].[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15]>C(N(CC)CC)C.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.[Cu]I>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:3]=1[NH2:4]
Reactant: Nc1c(Br)cc(C(F)(F)F)cc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)cc(Br)c1N
Yield: 92.2 %

Procedure:
To a solution of 7.54 g of 2-bromo-6-iodo-4-(trifluoromethyl)-aniline (21 mmol) in 70 ml triethylamine were added 723 mg of Pd(PPh3)2Cl2 (1 mmol), 196 mg of CuI (1 mmol) and 3.14 ml of ethinyltrimethylsilane (23 mmol). The reaction mixture was stirred for 3 h at rt before the triethylamine was removed under reduced pressure. Then DCM was added and the resulting suspension was filtered. The filtrate was then concentrated and the residue purified by chromatography (silica gel; c-hexane/EtOAc 19:1) to yield 6.51 g (94%) of 2-bromo-4-trifluoromethyl-6-trimethylsilanylethynyl-phenylamine as a dark brown liquid. 1H NMR (CDCl3, 300 MHz): δ 0.28 (s, 9H), 4.99 (br s, 2H), 7.51 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[NH2:19][CH:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH3:21]>C(#N)C>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:17])[C:6](=[O:18])[C:5]=2[NH:19][CH:20]([CH3:21])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=1
Reactant: CC(N)C(C)(C)C
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Solvent: CC#N
Product: COc1ccc(-c2c(NC(C)C(C)(C)C)c(=O)c2=O)cc1
Yield: 79.9 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.300 g, 1.22 mmol) and 2-amino-3,3-dimethylbutane (0.18 mL, 1.34 mmol) in acetonitrile (7 mL) were converted to the title compound (0.28 g, 80%) m.p.: 179-181° C.; 1H NMR (DMSO-d6) δ 8.56(br d,1H), 8.06(ABq,2H), 7.09(ABq,2H), 4.31(m,1H), 3.83(s,3H), 1.24(d,3H), 0.91(s,9H); IR (KBr) 3200, 2980, 1780, 1720, 1620, 1420, 1310, 1270, 1190, 1120, 1040, 840 cm−1; MS (m/z) 287 [M+].
Reaction SMILES: C1(C[N:8]2[CH2:26][CH2:25][C:11]3([CH2:16][CH2:15][N:14]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)C=CC=CC=1.C(O)(=O)C>C(O)C>[CH2:16]1[C:11]2([CH2:25][CH2:26][NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13][N:14]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1
Reactant: CC(C)(C)OC(=O)CN1CCC2(CC1)CCN(Cc1ccccc1)CC2
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CN1CCC2(CCNCC2)CC1

Procedure:
To a solution of 9.3 g (25.9 mmol) of the compound from Step E in 400 ml dry ethanol were added 1.5 ml acetic acid and 0.7 g Pd(II) hydroxide. The mixture was filled into an autoclave and hydrogenated at 50 atm and 50° C. for 18 h. The solvent was removed under reduced pressure, and the residue was stirred with saturated aqueous sodium bicarbonate solution. It was extracted five times with 100 ml tert.-butylmethylether followed by three extractions with 100 ml dichloromethane. The extracts were dried over sodium sulfate and concentrated in vacuo, separately. The first extract contained a mixture of compounds, whereas the pure title intermediate was obtaind from the following.
Reaction SMILES: [Cl:1][C:2]1[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]=1[NH:9][CH:10]([CH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25](=[O:34])[C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH2:20][CH2:19]2)[C:11]([O:13]C)=[O:12].ClC1C=NC=C(Cl)C=1C(N1C2C(=CC(CC(NC3C4(CCCCC4)C(=O)C=3)C(O)=O)=CC=2)CC1)=O>>[Cl:1][C:2]1[C:5](=[O:6])[C:4]([CH3:8])([CH3:7])[C:3]=1[NH:9][CH:10]([CH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25](=[O:34])[C:26]1[C:27]([Cl:33])=[CH:28][N:29]=[CH:30][C:31]=1[Cl:32])[CH2:20][CH2:19]2)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)NC1=C(Cl)C(=O)C1(C)C
Agent: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)NC1=CC(=O)C12CCCCC2
Product: CC1(C)C(=O)C(Cl)=C1NC(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)C(=O)O

Procedure:
The title compound was prepared from the compound of Example 30 in a similar manner to the compound of Example 2 as a white solid (78 mg, 61%). δH NMR (d6 DMSO) 8.82 (2H, s), 8.02 (0.88H, d) & 5.73 (0.12H, d), 8.74 (0.12H, d) & 7.19 (0.88H, s), 7.13 (0.88H, d) & 6.80 (0.12H, t), 4.56 (1H, br m), 3.74 (2H, t, J 8.1 Hz), 3.11 (4H, m), 0.82 (3H, s), 0.80 (3H, s). m/z (ES+, 70V) 508 (MH+).
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[C:21]=2[CH2:20][CH2:19]1>>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]3[N:25]=[C:26]4[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]4)=[C:22]([C:34]([F:36])([F:35])[F:37])[CH:23]=3)[CH2:13][CH2:12]2)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=CCCCOc1cc(C(F)(F)F)c2c(n1)NC(=O)CC2
Reactant: c1cc2c(c(N3CCNCC3)c1)CCCC2
Product: O=C1CCc2c(C(F)(F)F)cc(OCCCCN3CCN(c4cccc5c4CCCC5)CC3)nc2N1

Procedure:
In a manner similar to that of other examples above, 1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-piperazine was coupled by reductive amination to 4-(7-oxo-4-trifluoromethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 503.1 (Exact Mass: 502.26).
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[OH:75][B:76]([OH:87])[C:77]1[CH:85]=[CH:84][C:80]([C:81](O)=[O:82])=[CH:79][C:78]=1[F:86]>C(Cl)Cl>[C:37]([CH2:36][C:12]1([N:14]2[CH:18]=[C:17]([C:19]3[C:20]4[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:21]=4[N:22]=[CH:23][N:24]=3)[CH:16]=[N:15]2)[CH2:11][N:10]([CH:7]2[CH2:8][CH2:9][N:4]([C:81]([C:80]3[CH:84]=[CH:85][C:77]([B:76]([OH:87])[OH:75])=[C:78]([F:86])[CH:79]=3)=[O:82])[CH2:5][CH2:6]2)[CH2:13]1)#[N:38]
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)c6ccc(B(O)O)c(F)c6)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.0 g, 2.0 mmol) in methylene chloride (DCM) (10 mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.2 g, 2.6 mmol), N,N-diisopropylethylamine (1.1 mL, 6.1 mmol), and 4-(dihydroxyboryl)-3-fluorobenzoic acid (0.37 g, 2.0 mmol). The mixture was stirred at room temperature overnight. Solvents were removed under reduced pressure and the residue was purified using HPLC to give 0.54 g (41%) of the corresponding product {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid. LC-MS: 659.3 (M+H)+.