Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][CH:27]1[NH:31][C:30](=[O:32])[CH2:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:31]5[CH:27]([CH3:26])[CH2:28][CH2:29][C:30]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: CC1CCC(=O)N1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CCC3C)nn2)CC1
Yield: 11.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and 5-methylpyrrolidin-2-one (30 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (14 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[S:16][CH:15]=2)[N:11]([CH3:30])[N:10]=1.[Br:31]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=3)[S:16][C:15]=2[Br:31])[N:11]([CH3:30])[N:10]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1csc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(-c2ccc(OC(F)(F)F)cc2)sc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-[5-(4-trifluoromethoxyphenyl)thien-3-yl]-1H-1,2,4-triazole (0.26 g, 0.6 mmol) in glacial acetic acid (7 mL) was cooled to 6° C. Bromine (0.1 g, 32 μL, 0.6 mmol) was added to the reaction and allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with ether (3×30 mL). The combined ethereal extracts were washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL), aqueous sodium bisulphite (10% solution, 50 mL) and brine (70 mL), dried over magnesium sulphate and concentrated. Column chromatography gave the product (297 mg, 97%) as a yellowish solid: mp 135–136° C.; 1H NMR (CDCl3) δ 7.57 (d, 1H), 7.25–7.40 (m, 5H), 7.12 (t, 1H), 4.04 (s, 3H); EI/MS 533 m/e (M+).
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8](Cl)[N:7]=[CH:6][N:5]=1>C(OCC)C.CO>[Cl:3][C:4]1[N:5]=[CH:6][N:7]=[C:8]([NH2:2])[C:9]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: Nc1ncnc(Cl)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 74.9 %

Procedure:
A solution of 28% aqueous ammonium hydroxide (670 mL, 5.35 mol, 1.04 equiv) was added in a drop-wise fashion to a rapidly stirred solution of the 4,6-dichloro-5-nitropyrimidine solid (1000 g, 5.16 mol, 1.00 equiv) in diethyl ether (4000 mL) and methanol (670 mL). The addition was carried out over a period of 2 hours. Upon completion of addition, the resulting yellow solid was filtered off, washed with water and hexane, and dried under reduced pressure to give the title compound as a yellow solid (yield: 675 g). This crude solid was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 7.91 (broad s, 2H). MS (EI) for C4H3ClN4O2: 175 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:22]=1.[C:41]1([C:47]#[CH:48])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[N+:30]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:22]=[C:21]2[C:48]#[C:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([O-:32])=[O:31]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc([N+](=O)[O-])ccc21
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
5-Nitro-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: 0.16 g of triphenylphosphine, 0.54 g of tetrakis(triphenylphosphine)palladium(0) and 0.27 g of copper iodide are added to a solution, under argon, of 3 g of 3-iodo-5-nitro-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 200 ml of acetonitrile. After stirring for 10 minutes, 1.57 ml of phenylacetylene and 2 ml of triethylamine are added, and the reaction mixture is then refluxed for 16 hours. After cooling to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue is taken up in 150 ml of dichloromethane and then washed with 2 times 120 ml of water. The aqueous phases are pooled and extracted with 100 ml of dichloromethane. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue is purified by chromatography under argon pressure (50 kPa), on a column of 200 g of silica (particle size 40-63 μm), eluting successively with pure cyclohexane then with cyclohexane/ethyl acetate (98/2; 97/3; 95/5; 90/10 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. 2.31 g of 5-nitro-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole are thus obtained in the form of a brown solid melting at 88° C.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]([NH:24][NH2:25])=[S:23])[CH2:18][CH2:17]1>C(O)C.C(Cl)Cl>[CH3:15][N:16]1[CH2:17][CH2:18][N:19]([C:22](=[S:23])[NH:24][N:25]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)[CH2:20][CH2:21]1
Reactant: CN1CCN(C(=S)NN)CC1
Reactant: O=C(c1ccccc1)c1ccnnc1
Solvent: CCO
Solvent: ClCCl
Product: CN1CCN(C(=S)NN=C(c2ccccc2)c2ccnnc2)CC1
Temperature: 65 °C
Yield: 42.6 %

Procedure:
A mixture of phenyl-pyridazin-4-yl-methanone (12; Synthon A, 2.3 g, 12.4 mmol) and 4-Methylpiperazine-1-carbothioic acid hydrazide (6; Synthon B, 2.82 g, 16.18 mmol) in ethanol (7.5 mL) was heated to 65° C. for 5 h under N2 in a 50 mL pyrex tube equipped with a screw cap. The mixture remained heterogeneous during the heating and a brown suspension resulted at the end of the reaction. The mixture was diluted with CH2Cl2 (7.5 mL) and was chromatographed on silica gel that was eluted with MeOH/CH2Cl2 (2.5-5%) to give 1.8 g of a yellow foamy solid 1A (99.3% pure by HPLC); m.p. 141-143° C. (m.p. of a crystalline sample 143-145). TLC (CH2Cl2/MeOH/NH4OH: 95/5/0.5): Rf=0.6, product is visibly yellow, UV and Dragendorff stain active. MS (ESI+): [M+H]+=340.93. HRMS: m/z calcd. for C17H21N6S ([M+H]+): 341.15429. found: 341.15501. 1H NMR (300 MHz, CDCl3), δ ppm: 2.38 (s, 3H), 2.61 (t, 4H, J=5.0 Hz), 4.12 (t, 4H, J=5.0 Hz), 7.29 (m, 3H), 7.63 (m, 3H), 8.64 (s, 1H), 9.14 (dd, 1H, J=5.7 Hz, J′=1.5 Hz), 9.44 (dd, 1H, J=2.4 Hz, J′=1.5 Hz). 13C NMR (75.4 MHz, CDCl3), δ ppm: 45.75, 51.64, 54.75, 123.30, 128.29, 128.39, 130.40, 131.10, 134.86, 143.94, 148.31, 151.31, 181.49.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]([O:14]CC)=[O:13])=[N:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Li+].[OH-].Cl>C1COCC1.CO>[N:1]1([CH2:6][C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[N:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)c1ncc(Cn2ccnc2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ncc(Cn2ccnc2)s1

Procedure:
A solution of ethyl 5-((1H-imidazol-1-yl)methyl)thiazole-2-carboxylate (143 mg, 0.60 mmol) and 1 M LiOH solution (1.2 ml, 1.2 mmol) in THF (2 ml) and MeOH (1 ml) was stirred at RT for 1.5 h. Some 1 M HCl was added until pH of the mixture was about 8. Solvents were evaporated and thus obtained crude product was used as such in the next synthesis step. 1H-NMR (400 MHz; d6-DMSO): δ 5.28 (s, 2H), 6.92 (s, 1H), 7.22 (s, 1H), 7.54 (s, 1H), 7.79 (s, 1H).
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].[Li]CCCC.[CH3:29][O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=O.O>C1COCC1>[CH3:29][O:30][C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[C:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CCCCC=O
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCCC=C(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To a stirred suspension of isopropyltriphenylphosphonium bromide (10.9 g, 28.3 mmol) in THF (60 mL) was added dropwise n-BuLi (12.0 mL, 2.5 M solution in hexanes, 30.0 mmol) at 0° C. under N2. The resulting solution was stirred at this temperature for 30 min and cooled to −78° C. A solution of 6-oxo-hexanoic acid methyl ester (3.95 g, 19.7 mmol) in THF (10 mL) was added quickly. The resulting mixture was then allowed to warm to room temperature and stirred overnight. Water (30 mL) was added. The aqueous phase was extracted with hexane. The combined organic phases were washed with saturated aqueous NH4Cl and brine and dried. Concentration and purification of the residue by flash chromatography on silicagel (hexane:ethyl acetate, 10:1) afforded 7-methyl-oct-6-enoic acid methyl ester (3.39 g, 72%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.08 (1H, m), 3.64 (3H, s), 2.29 (2H, t, J=7.2 Hz), 1.97 (2H, m), 1.66 (3H, s), 1.62 (2H, m), 1.58 (3H, s), 1.36 (2H, m); 13C NMR (75 MHz, CDCl3) δ 174.26, 140.05, 131.80, 124.27, 51.67, 34.29, 29.60, 27.89, 25.97, 24.87, 17.94.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1>C(N(CC)CC)C.[Pd].CCO>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[C:4]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:17]=1)=[CH:3][CH:2]=[N:7]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccnn3ccnc23)cc1
Reaction time: 12 h
Yield: 93.3 %

Procedure:
To a mixture of tert-butyl 4-(6-chloroimidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate (0.1 g, 0.28 mmol) from 1a and EtOH (4 mL) in a 500 ml PARR bottle was added 10% Pd/C (0.02 g) and 2 drops of triethyl amine. The PARR bottle was then charged with H2 at 55 psi and allow to shake at room temperature for 12 hours. The reaction mixture was then filtered and the filtrate concentrated in vacuo to give 0.085 g of crude tert-butyl 4-(imidazo[1,2-b]pyridazin-8-ylamino)phenylcarbamate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C-:9]#[N:10].[Na+].O>CS(C)=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: [C-]#N
Reactant: Cc1ccc(F)nc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(C#N)nc1
Yield: 30 %

Procedure:
A solution of 2-fluoro-5-methylpyridine (CAN: 2369-19-9, 10 g, 90 mmol) and sodium cyanide (8.8 g, 180 mmol) in DMSO (15 mL) was heated to 150° C. for 48 h. Then water was added, the resulting mixture was extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with sodium hypochlorite solution and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 40 g, 10% ethyl acetate in petroleum ether) to yield the title compound (3.2 g, 27 mmol, 30.1%) as yellow solid; MS (EI): m/e=119.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]([CH3:48])[CH2:36][CH2:37][O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[NH2:42].Cl>C(O)(C)C>[CH3:48][N:35]([CH3:34])[CH2:36][CH2:37][O:38][C:39]1[CH:40]=[C:41]([NH:42][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:43]=[CH:44][C:45]=1[O:46][CH3:47]
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COc1ccc(N)cc1OCCN(C)C
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)cc1OCCN(C)C

Procedure:
A mixture of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (prepared according to a procedure similar to that described in Example 27, Step C) and 3-{[2-(dimethylamino)ethyl]oxy}-4-(methyloxy)aniline were heated in isopropanol with catalytic conc. aq. HCl using conditions similar to those described in Example 27, Step D. HRMS C35H32N7O3F2 (M+H)+ calcd 636.2535, found 636.2527.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[OH:5].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:24]([O:26][CH3:27])=[O:25])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(O)CCN)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NCCC(O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3-amino-1-(3,4-dimethoxyphenyl)-1-propanol (1.27 g, 6.02 mM), triethylamine (0.84 g, 8.30 mM), and methyl chloroformate (0.59 g, 6.25 mM) were dissolved in dried tetrahydrofuran (80 ml) and stirred at room temperature for 5.5 hours. The solution obtained was poured into ice water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product of 1-(3,4-dimethoxyphenyl)-3-(methoxycarbonylamino)-1-propanol as a yellow oil. Next, the crude product was dissolved in dried benzene (5 ml). The mixture was dropped into a solution of sodium hydride (60%) (0.24 g, 6.04 mM) in dried benzene (40 ml) at room temperature, water was added into the reaction solution and the mixture stirred at that temperature for 24 hours, which was then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product as a brown solid. The crude product was washed with ether to obtain the above-described compound 0.86 g (yield 63.1%) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][C@@H:14]([OH:17])[CH2:13]1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:16][CH2:15][C@@H:14]([O:17][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O)C1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COc1cc([N+](=O)[O-])ccc1N1CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 0 °C
Yield: 99.4 %

Procedure:
Dissolve the crude (R)-1-(2-methoxy-4-nitro-phenyl)-pyrrolidin-3-ol (10.9 g, 45.5 mmol) in dry pyridine (50 mL) and chill to 0° C. Add chloro-triisopropyl-silane (19.8 mL, 91 mmol) dropwise and then heat to 80° C. overnight. Remove the pyridine via reduced pressure and then wash the crude material with NaHSO3 solution and extract with EtOAc (3×100 mL). Combine the organic solutions, then dry and concentrate to give the crude product. Purify over a silica plug with hexanes (300 mL) and flush with 10% EtOAc in hexanes (800 mL) to give the title compound as a reddish oil (17.85 g, 99%). MS/ES m/z 395.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:45][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: NC1CCCC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
6.4 g (0.02 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 100 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 2.54 ml of N-ethylmorpholine and 2.62 ml of isobutyl chloroformate were added and the mixture was stirred at -10° C. for 20 minutes. 1.98 ml of cyclopentylamine were then added and the mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was then evaporated and the product which crystallised on the addition of water was extracted into ethyl acetate. The organic layer was washed neutral, dried over sodium sulphate and evaporated, the product crystallising on the addition of ether. There were obtained 4.8 g (71%) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclopentylamide of melting point 118°-119° C.; [α]D20 =-93.5° (c=1.0228% in methanol).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[N:5]=1)(=[O:3])[CH3:2].[CH2:11]([OH:14])[C:12]#[CH:13]>C(N(CC)CC)C.O.[Cu]I>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:13][C:12]#[C:11][OH:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(Br)n1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(CC#CO)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A suspension of 3 g (15.1 mmol) of 2-acetyl-6-bromopyridine, 0.89 g (15.9 mmol) of propargyl alcohol, 0.078 g of CuI, 300 mg of PdCl2 (P(Ph)3)2 in 60 ml of triethylamine was stirred under nitrogen at room temperature for 6 h. The mixture was diluted with water, extracted with ether, and the organic layer was washed with water (2x), brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo and the residue was purified by MPLC (silica gel 60, hexane/ethyl acetate, 1:1) to afford 1.3 g (50%) of 2-acetyl-6-(3-hydroxy-2-propynyl)pyridine, as a solid product.
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1.N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:20]3[O:21][C:17]4[CH:16]=[CH:15][C:14]([Cl:13])=[CH:25][C:18]=4[CH:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2cc(Cl)ccc2o1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-chlorobenzofuran-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 6.43-6.48 (m, 1H), 6.52 (s, 1H), 6.57-6.62 (m, 1H), 6.76 (d, J=2.0 Hz, 1H). MS (DCI/NH3) m/z 331.
Reaction SMILES: C([O:4][C:5]([CH3:7])=[CH2:6])(=O)C.N(OC(C)(C)C)=O.[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:17]=1N>CC(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:17]=1[CH2:4][C:5](=[O:6])[CH3:7]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: C=C(C)OC(C)=O
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.2 %

Procedure:
In a 1.5 l sulfonation flask equipped with mechanical stirring, cooling funnel, dropping funnel and thermometer under nitrogen at ambient temperature filled with acetone (240 ml), were added isopropenyl acetate (66 ml, 0.60 mol), tert-butyl nitrite (40 ml, 0.30 mol) and cupric sulfate pentahydrate (2.5 g, 0.001 mol). The resulting light green-blue suspension is stirred for 15 min at ambient temperature. A solution of 2,4,6-trichloroaniline (40 g, 0.20 mol), dissolved in acetone (320 ml) was added dropwise over a period of 2 hours. During the addition, bubbling observed, temperature rose to 30° C. and the mixture turned green. 1 Hour after the addition, an amber solution was obtained. The mixture was stirred for 6 hours. Completion of the reaction was confirmed by GC-MS. The crude mixture was concentrated under reduce pressure to remove most of the acetone and the residue was dissolved in ethyl acetate (300 ml) and wash with 1M hydrochloric acid (2×300 ml), water (2×300 ml) potassium carbonate solution (300 ml) followed by water (300 ml). Combined basic aqueous were re-extracted with of ethyl acetate (150 ml). Combined organics were dried over sodium sulfate, and the organics were concentrated under reduced pressure to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one (53 g) as a dark brown oil. The crude was dissolved again in ethyl acetate (200 ml) and washed with 1M sodium hydroxide (300 ml) 1M hydrochloric acid (100 ml) and water (200 ml). The organic layers were dried and evaporated to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one 49 g dark brown oil which crystallized.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:39]=[CH:38][C:28]([CH2:29][P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:27][C:26]=3[O:40][CH3:41])[N:15]=2)=[C:6]2[C:10]=1[CH2:9][N:8]([CH3:11])[C:7]2=[O:12].[C:42]([O:46][C:47](=[O:55])[CH2:48][N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)([CH3:45])([CH3:44])[CH3:43]>>[CH2:32]([O:31][P:30]([CH2:29][C:28]1[CH:38]=[CH:39][C:25]([NH:24][C:16]2[N:15]=[C:14]([NH:13][C:5]3[CH:4]=[CH:3][C:2]([N:52]4[CH2:51][CH2:50][N:49]([CH2:48][C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:55])[CH2:54][CH2:53]4)=[C:10]4[C:6]=3[C:7](=[O:12])[N:8]([CH3:11])[CH2:9]4)[C:19]([C:20]([F:23])([F:21])[F:22])=[CH:18][N:17]=2)=[C:26]([O:40][CH3:41])[CH:27]=1)([O:34][CH2:35][CH3:36])=[O:37])[CH3:33]
Reactant: CC(C)(C)OC(=O)CN1CCNCC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCN(CC(=O)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 199 using Diethyl [4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl) pyrimidin-2-yl}amino)-3-methoxybenzyl]phosphonate and piperazine-1-acetic acid tert-butyl ester.MS (ES+): m/z 778.42 (100) [MH+]; HPLC: tR=0.86 min (UPLC, purity).