Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH:52]([N:55]=[C:56]=[O:57])([CH3:54])[CH3:53]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:56]([NH:55][CH:52]([CH3:54])[CH3:53])=[O:57])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N=C=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: O=C([O-])C(F)(F)F
Product: CC(C)NC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and isopropyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.06 (d, 6.5 Hz, 6H), 1.39 (s, 6H), 1.82 (m, 1H), 2.19-2.58 (m, 3H), 3.74 (m, 1H), 4.12 (s, 2H), 4.32 (m, 1H), 4.87 (d, 15 Hz, 1H), 5.01 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H). FAB-MS: calculated for C40H45N5 O5 675; found 676(M+H, 80%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([OH:24])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[Cl:33][C:34]([Cl:38])([Cl:37])[CH2:35]O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:35][C:34]([Cl:38])([Cl:37])[Cl:33])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C
Reaction time: 1 h

Procedure:
6.2 g of dicyclohexylcarbodiimide were introduced into a solution of 7.15 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 80 mg of 4-dimethylamino-pyridine in 35 ml of methylene chloride and the reaction mixture was stirred for 10 minutes after which 4.5 of 2,2,2-trichloroethanol were added. The mixture was stirred for 1 hour and was filtered. The filtrate was washed with N hydrochloric acid, then with water until neutral, dried and evaporated to dryness. The 14 g of oil residue were chromatographed over silica gel and eluted with a 97-3 mixture of benzene-ethyl acetate to obtain 9 g of tert.butyl (1R,cis) 2,2-dimethyl-3-(2,2,2-trichloroethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 70-71° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[NH2:6][CH:7]([C:12]([OH:14])=[O:13])CCSC.[O-2].[Ca+2:16].[Ca]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:6][CH2:7][C:12]([O-:14])=[O:13].[Ca+2:16]
Reactant: NCC(=O)O
Reactant: CSCCC(N)C(=O)O
Agent: [Ca+2]
Agent: [Ca]
Agent: [O-2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
About 7.00 grams of water used to dissolve 86.5 grams of glycine and 70 grams of DL-methionine. Next, 47 grams of calcium oxide, which was 70% calcium by weight, was added. The solution was continually stirred until all of the calcium oxide appeared to be dissolved. The reaction formed a calcium bisglycinate chelate or complex solution.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(C[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3Cl)C=2N=1)(C)(C)C.C1(C2CCNC2)C=CC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH:24]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: c1ccc(C2CCNC2)cc1
Product: CC(C)(C)c1nc(N2CCC(c3ccccc3)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chlorobenzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-phenylpyrrolidine. MS (m/e): 447.4 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[CH:5]=[C:6]([I:10])[C:7]=1[O:8][CH3:9].Br[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=[CH:23]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[O:18]=[C:12]1[NH:13][C:14](=[O:17])[CH:15]=[CH:16][N:11]1[C:4]1[CH:5]=[C:6]([I:10])[C:7]([O:8][CH3:9])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH:24]=[CH:23]3)[CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Reactant: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1c(I)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2cc(NS(C)(=O)=O)ccc2c1
Yield: 11 %

Procedure:
A mixture of the product from Part B 1-(3,5-diiodo-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (118 mg, 0.25 mmol), the product from Example 2A, Part B (87 mg, 0.25 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride CH2Cl2 complex (10.21 mg, 0.013 mmol) and sodium carbonate (0.250 ml, 0.25 mmol) in toluene (1.0 ml) and ethanol (1.0 ml) was sparged with nitrogen for 5 min and microwaved at 100° C. for 30 min. The mixture was cooled and partitioned with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, filtered and evaporated. The residue was chromatographed on silica eluting with ethyl acetate/hexane (2:3 to 4:1) to give the title compound (16 mg, 11%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3 H) 3.35 (s, 3 H) 5.67 (d, J=8.09 Hz, 1 H) 7.42 (dd, J=8.82, 2.21 Hz, 1 H) 7.59 (d, J=2.57 Hz, 1 H) 7.73 (m, 2 H) 7.81 (d, J=8.09 Hz, 1 H) 7.95 (m, 3 H) 8.09 (s, 1 H) 10.06 (s, 1 H) 11.47 (s, 1 H). MS (ESI−) m/z 562 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24]O)[N:22]=1)=[CH:5]2.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:50]I>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[S:19][CH2:20][C@@H:21]([CH2:23][CH2:24][I:50])[N:22]=1)=[CH:5]2
Reactant: II
Reactant: OCC[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCOCC4)c3[nH]2)=N1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cc(NC2CCOCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Reaction time: 8 h
Yield: 39.9 %

Procedure:
The compound obtained in Example 13 (3.7 g, 10.2 mmol) was dissolved in tetrahydrofuran (100 ml). Imidazole (2.1 g, 30.6 mmol), triphenylphosphine (4.0 g, 15.3 mmol) and iodine (3.9 g, 15.3 mmol) were added, and stirred for 8 h at 0° C.˜room temperature. After completion of the reaction, ethyl acetate (100 ml) was added, and the reaction mixture was washed with water (100 ml×2). The organic layer was concentrated and the residue was purified by column chromatography to give the title compound (2.0 g, 4.07 mmol, Yield 40%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.[NH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCCc1c[nH]c2ccccc12
Temperature: 110 °C
Yield: 55.4 %

Procedure:
A mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (124.5 mg, 0.44 mmol), tryptamine (70.7 mg, 0.44 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1.5 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 100 mg (55%) of yellow solid mp 278-280° C.; HRMS (ESI) m/z calcd for C20H16BrN3O2 408.03531. found 408.03493 (M+H)+1, Analysis for C20H16BrN3O2; Calcd: C, 58.55; H, 3.93; N, 10.24. Found: C, 58.34; H, 3.63; N, 10.21.
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[P:20](Cl)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34].Cl>O1CCCC1.C(#N)C>[P:20]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:20]([O:37][C:38]3[C:39]([C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:40][C:41]([CH3:48])=[CH:42][C:43]=3[C:44]([CH3:47])([CH3:46])[CH3:45])[O:21][C:22]3[C:23]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:24][C:25]([CH3:32])=[CH:26][C:27]=3[C:28]([CH3:29])([CH3:30])[CH3:31])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([O:37][C:38]1[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:42][C:41]([CH3:48])=[CH:40][C:39]=1[C:49]([CH3:52])([CH3:51])[CH3:50])[O:21][C:22]1[C:27]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:26][C:25]([CH3:32])=[CH:24][C:23]=1[C:33]([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Cc1cc(C(C)(C)C)c(OP(Cl)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Product: Cc1cc(C(C)(C)C)c(OP(Oc2ccc(C(C)(C)c3ccc(OP(Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)Oc4c(C(C)(C)C)cc(C)cc4C(C)(C)C)cc3)cc2)Oc2c(C(C)(C)C)cc(C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
A solution of 0.9 grams of 4,4'-isopropylidenebisphenol (0.004 mol) in 50 ml of dry tetrahydrofuran was added to a reaction vessel equipped with stirring and heating means. While stirring the 4,4'-isopropylidenebisphenol solution under nitrogen, 0.19 gram (0.008 mol) of sodium hydride, as a 50 weight percent dispersion mineral oil was added to the 4,4-isopropylidenebisphenol solution and the resulting mixture was stirred at 55° C. for one hour. The reaction mixture was cooled to room temperature and a solution of bis(2,6-di-t-butyl-4-methylphenyl) phosphorochloridite (4.0 grams, 0.008 mol) in 25 ml of tetrahydrofuran was added to the reaction mixture and the mixture was stirred for three hours. The reaction product was then acidified with 1N HCl and filtered. The filtrate was heated to remove the solvent, and an oily reaction product was obtained. This oil was stirred with 50 ml of acetonitrile for one hour. The resulting white powder was recovered by filtration and dried. The product yield of tetrakis(2,6-di-t-butyl-4-methylphenyl)-4,4'-isopropylidenebisphenyl diphosphite was 3.72 grams. The molecular weight, FD/MS was 1164. NMR data obtained was, (CDCl3): 1.44 (S, 72H), 2.23 (S, 12H), 6.01 (d, J=8.4, 4H), 6.69 (d, J=8.4, 4H), 7.02 (S,8H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].BrBr.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>O1CCOCC1.C(#N)C>[CH3:14][C:15]1[N:16]([CH2:2][C:1]([C:4]2[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=2)[C:7]#[N:8])=[O:3])[CH:17]=[CH:18][N:19]=1
Reactant: Cc1ncc[nH]1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: BrBr
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1nccn1CC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-acetylbenzonitrile (50 g, 0.345 mol) is dissolved in dioxane (600 ml) with stirring at room temperature, bromine (17.7 ml, 0.345 mol) is added in and the mixture is stirred for 30 minutes. The dioxane is removed in vacuo to give a solid which is dissolved in acetonitrile (300 ml). 2-Methylimidazole (28.3 g, 0.345 mol) is added to the solution and the mixture is stirred for 1 hour, the temperature of the mixture rising to 45° C. The precipated solid is filtered off, washed with acetonitrile, and slurried with methanol for 1 hour. After filtering to remove undissolved solid, the filtrate is evaporated in vacuo to leave a solid which is dried in vacuo at 40° C. to give the title compound, m.s. 369 (MH+).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.C(NS(=O)(=O)[O:33][CH2:34][C@@H:35]1[C@@H:42]2[C@@H:38]([O:39][C:40]([CH3:44])([CH3:43])[O:41]2)[C@H:37]([N:45]2[CH:53]=[N:52][C:51]3[C:46]2=[N:47][CH:48]=[N:49][C:50]=3Cl)[O:36]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(O)C>[C@@H:3]1([N:2]([CH3:1])[C:50]2[N:49]=[CH:48][N:47]=[C:46]3[C:51]=2[N:52]=[CH:53][N:45]3[C@H:37]2[C@@H:38]3[O:39][C:40]([CH3:44])([CH3:43])[O:41][C@@H:42]3[C@@H:35]([CH2:34][OH:33])[O:36]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CN[C@H]1CCc2ccccc21
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(=O)(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@H]2n1cnc2c(Cl)ncnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]2OC(C)(C)O[C@H]21)[C@H]1CCc2ccccc21
Temperature: 150 °C
Yield: 55 %

Procedure:
A suspension of (1S)-N-methylindan-1-amine (67.8 mg, 0.461 mmol), [(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl tritylsulfamate (200 mg, 0.309 mmol) and DIPEA (0.160 mL, 0.919 mmol) in ethanol (3.0 mL) was heated at 150° C. for 600 s using microwave irradiation. The residue was purified via flash chromatography (0 to 100% EtOAc/DCM) to afford the title compound as a brown oil (74.3 mg, 55%).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[C-:20]#[N:21].[Na+]>C(#N)C>[C:20]([C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1)#[N:21]
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: Cn1nnnc1-c1cn(C)c2cc(C#N)ccc2c1=O
Reaction time: 70 h

Procedure:
A mixture of 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (5.25 g), sodium cyanide (1.0 g), crown ether (18-crown-6, 5.4 g) and acetonitrile (200 ml) was stirred and boiled under reflux for 79 hours, left at ambient temperature for 70 hours, and boiled under reflux for 24 hours. The mixture was cooled and filtered. The residue was boiled with industrial methylated spirit (200 ml) and the mixture filtered while hot. The residue was further extracted twice with boiling 50% aqueous industrial methylated spirit (400 ml, then 200 ml). Each hot extract precipitated a solid when cooled. The three solids were combined and recrystallised from 50% aqueous industrial methylated spirit to give a crude product. This product was purified by high pressure liquid chromatography on silica, using dichloromethane:methanol 9:1 as the eluent. The eluent was evaporated to give a residue which was recrystallised from 30% aqueous industrial methylated spirit to give the novel compound 7-cyano-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone, m.p. 301°-303°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])(C)C.Cl.C([O-])(O)=O.[Na+].C(=O)(ON1C(=O)CCC1=O)OCC1[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>O1CCOCC1.O>[CH:36]1[C:35]2[CH:4]([CH2:1][O:5][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([C:15]([OH:17])=[O:16])[CH2:9]3)=[O:7])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]=2[CH:39]=[CH:38][CH:37]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.50 g, 6.17 mmol, Example #13, Step G) in 1,4-dioxane (10 mL) was added aqueous HCl (4N in 1,4-dioxane (4.62 mL, 18.5 mmol). The reaction mixture was heated at about 60° C. for about 16 h before being allowed to cool to ambient temperature. To the mixture was added NaHCO3 (2.07 g, 24.7 mmol) and water (10.0 mL) followed by (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (4.16 g, 12.3 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was acidified to about pH 1 with aqueous 1N HCl and was extracted with EtOAc (75 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (40 g column) eluting with a gradient of 1-5% MeOH in DCM to give 1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-methylpiperidine-3-carboxylic acid (0.72 g, 31%) as a clear oil: LC/MS (Table 2, Method a) Rt=2.44 min; MS m/z: 366 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][C:40](O)=[O:41])=[N:37][CH:38]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][C:36]3[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][N:37]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(Cl)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (5-chloro-pyridin-2-yl)-acetic acid (18.8 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (0.16 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (64%, 30 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 129.6 %

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.00 g, 4.97 mmol, 1.0 equiv) and Et3N (1.06 g, 10.5 mmol, 2.1 equiv) in DCM (15 mL) was added dropwise MsCl (0.85 g, 7.40 mmol, 1.5 equiv) at 0° C. Then the reaction mixture was stirred at room temperature for 3 h. After the mixture was washed with brine, the organic layer was separated, dried over Na2SO4, filtered, and concentrated to give 1.8 g of the crude product, which was used for the nest step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:4]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]1[CH2:25][C:26]#[CH:27].I[C:29]1[CH:30]=[C:31]2[C:44](=[CH:45][CH:46]=1)[CH2:43][C@:33]1([C:41]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]1=[O:42])[CH2:32]2.C(N(CC)CC)C>CN(C=O)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>[O:1]=[C:2]1[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:4]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:3]1[CH2:25][C:26]#[C:27][C:29]1[CH:30]=[C:31]2[C:44](=[CH:45][CH:46]=1)[CH2:43][C@:33]1([C:41]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]1=[O:42])[CH2:32]2
Reactant: C#CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)CC12CCCCCC2
Reactant: O=C1Nc2ncccc2[C@]12Cc1ccc(I)cc1C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2(CCCCCC2)N(CC#Cc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12CCCC2
Temperature: 50 °C

Procedure:
A stirred suspension of tert-butyl 16-oxo-15-prop-2-yn-1-yl-6,15-diazadispiro[4.2.6.2]hexadecane-6-carboxylate (110 mg, 0.294 mmol, described in Intermediate 23), (2R)-5-iodo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (106 mg, 0.294 mmol, described in Intermediate 27), tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.029 mmol), copper(I)iodide (23 mg, 0.121 mmol), and triethylamine (0.082 mL, 0.588 mmol) in degassed DMF (1.5 mL) was heated at 50° C. for 30 min. The reaction was quenched with water (30 mL), partitioned with saturated NaHCO3 solution (30 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to yield the title compound. MS: m/z=609 (M+1).
Reaction SMILES: O[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]([CH3:15])=[O:14].N1CCCC1>C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:15])[CH:2]([CH3:11])[C:3](=[O:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: CC(O)C(=O)c1ccccc1
Reactant: CC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC1C(=O)c2ccccc2OC1(C)C

Procedure:
A solution of 2-hydroxypropiophenone (500 ml, 3.64 mol), acetone (400 ml), and pyrrolidine (150 ml, 1.8 mol) in toluene (1000 ml) was heated at 85° C. for 66 hours. The cooled solution was then washed successively with water, aqueous hydrochloric acid and aqueous sodium hydroxide solution. The toluene layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/heptane (50/50), to give 81 g of 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil, a compound of formula (3 a) ; 1H NMR (CDCl3): δ 1.3 (d, 3H) , 1.4 (s,3H), 1.6 (s,3H), 2.5-3.0 (q,1H), 6.8-8.1 (m,4H).