Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.[O:18]=[S:19]1(=[O:36])[CH2:24][CH2:23][N:22]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:21]2=[N:20]1>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:35][C:32]2[CH:31]=[CH:30][C:29]([C@H:28]3[C:21]4=[N:20][S:19](=[O:36])(=[O:18])[CH2:24][CH2:23][N:22]4[CH2:25][CH2:26][CH2:27]3)=[CH:34][CH:33]=2)=[CH:11][CH:10]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4ccc(Cl)cc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.9 %

Procedure:
Diacetoxycopper (1037 mg) was added to a mixture of triethylamine (1.983 mL), 4-chlorophenylboronic acid (1339 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (800 mg) and in DMF (dry) (30 ml). The mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 15 hr. Then 4-chlorophenylboronic acid (1339 mg) and diacetoxycopper (1037 mg) were added and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube for 2 days. The insoluble material was removed by filtration, and the filtrate was diluted with water, and extracted with EtOAc. The organic layer was washed with 0.1N NaOH aq., dried over anhydrous magnesium sulfate. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) then crystallized from THF/IPE to give the title compound (177 mg) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[O:11][C:12]1[C:20]2[N:19]=[N:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.ClCCl>CS(C)=O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:6][C:5]=1[O:11][C:12]1[C:20]2[N:19]=[N:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc2c1nnn2Cc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cccc2c1nnn2Cc1ccc(OC)cc1
Temperature: 100 °C

Procedure:
To a solution of EXAMPLE 342D (650 mg) in dimethylsulfoxide (12 mL) was added piperazine (618 mg). The solution was heated at 100° C. for one hour, cooled, added to dichloromethane, extracted with water three times, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under vacuum.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[C:28]([Cl:33])[N:27]=1.CC1C=CC(C)=CC=1>ClCCl>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)(=[O:14])=[O:15])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:29]=[C:28]([Cl:33])[N:27]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: Nc1cc(Cl)nc(Cl)c1
Solvent: ClCCl
Solvent: Cc1ccc(C)cc1
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(Cl)nc(Cl)c2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (1 g), 2,6-dichloropyridin-4-amine (760 mg) and p-xylene (10 mL) was heated at 135° C. with stirring overnight. Upon cooling to room temperature, the mixture was dissolved in dichloromethane, washed with 2 N HCl (2×) and brine, concentrated in vacuo to give a crude product of N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide. A small portion of this crude product was purified by HPLC to give N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitro-benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 8.90 (s, 1H), 8.50 (d, 2H), 8.8.41 (d, 1H), 8.30 (s, 2H), 7.88-7.78 (m, 27.65 (d, 1H), 7.47-7.37 (m, 2H); MS (EI) m/z for C19H12Cl2N6O4S: 491.1, 493.1 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.C(N(CC)C(C)C)(C)C.[N:43]1[CH:48]=[CH:47][N:46]=[CH:45][C:44]=1[C:49](Cl)=[O:50]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:49]([C:44]4[CH:45]=[N:46][CH:47]=[CH:48][N:43]=4)=[O:50])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: O=C(Cl)c1cnccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)c2cnccn2)C3)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0493 g, 0.000129 mol) in dry N,N-Dimethylformamide (0.610 mL, 0.00788 mol) was added N,N-Diisopropylethylamine (0.0684 mL, 0.000393 mol) cooled at 0° C., added Pyrazine-2-carbonyl chloride (0.0312 g, 0.000219 mol), warmed to room temperature, and stirred overnight. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.98-8.91 (m, 1H), 8.80 (dd, J=5.3, 2.6, 1H), 8.74 (d, J=1.4, 1H), 8.64 (d, J=12.3, 1H), 8.18 (dd, J=34.9, 8.7, 2H), 7.47 (dd, J=20.0, 8.8, 2H), 6.20-6.09 (m, 1H), 4.75 (d, J=25.1, 2H), 3.88 (t, J=5.0, 1H), 3.79-3.60 (m, 5H), 3.49 (d, J=4.0, 4H), 3.18-3.02 (m, 2H), 2.77 (s, 2H), 1.06 (dd, J=13.3, 7.0, 3H). LC/MS-m/z+489.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][S:4]1)[CH3:2].C(C1SC2C(O)=NC=NC=2C1)C.O=P(Cl)(Cl)[Cl:27]>ClCCCl.C(N(C(C)C)CC)(C)C>[Cl:27][C:10]1[C:11]2[CH:3]([CH2:1][CH3:2])[S:4][CH2:5][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCC1SCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Agent: CCC1Cc2ncnc(O)c2S1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC1SCc2ncnc(Cl)c21
Yield: 28 %

Procedure:
To a solution of a mixture of 5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-ol and 6-ethyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (2.32 g, 12.8 mmol) in 1,2-dichloroethane (50 mL) and diisopropylethylamine (4 mL) was added POCl3 (4 mL), and the mixture was refluxed overnight. The solvent was removed and the residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (9:1-4:1) to give 4-chloro-5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidine (0.49 g, 28%). 1H NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 4.44 (m, 1H), 4.32-4.00 (m, 2H), 2.08 (m, 1H), 1.75 (m, 1H), 0.93 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1.Cl[CH2:35][C:36]1[CH:37]=[CH:38][C:39]2[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=2[CH:51]=1>>[F:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH:16]2[O:28][CH2:35][C:36]2[CH:37]=[CH:38][C:39]3[O:44][CH2:43][C:42](=[O:45])[N:41]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[C:40]=3[CH:51]=2)=[CH:13][CH:14]=1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3c(F)cccc3F)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4c(F)cccc4F)cc3)cc21

Procedure:
Analogously to Method D, 0.540 g of tert-butyl 4-{4-[3-(2,6-difluorophenoxy)propoxy]phenyl}-3-hydroxypiperidine-1-carboxylate and 0.350 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.18 (1:1 EtOAc-heptane); Rt=5.94.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:14])([NH2:13])[CH2:11][CH3:12].ClC1C=CC(CO)=CC=1CCO>C(O)C>[CH2:11]([C:10]1[S:14][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:13]=1)[CH3:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCC(N)=S
Agent: OCCc1cc(CO)ccc1Cl
Solvent: CCO
Product: CCOC(=O)c1csc(CC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 3-bromo-2-oxopropanoate (24.7 mL) was added dropwise over 10 min to a solution of propanethioamide [Carboxylic Acid 1, step a] (15.8 g) in ethanol (150 mL) at 0-10° C. under nitrogen. When the addition was complete the mixture was stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo, the residue diluted with water and extracted into ethyl acetate (×3). The combined extracts were washed with brine, dried over magnesium sulfate, filtered and the solvent removed. The crude product was purified by flash silica chromatography, elution gradient 10, 15 and 20% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound as a pale green solid. Yield 16.0 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[CH:15][C:16]4[O:17][CH2:18][CH2:19][O:20][C:21]=4[C:12]=3[O:11][CH2:10]2)[C:2]1=[O:22].[NH:23]1[C:31]2[C:26](=CC=C[CH:30]=2)[C:25]2([C:43]3[C:34](=CC4OCCOC=4C=3)OC2)C1=O.Br.BrCC1C=CC=CN=1.BrCC1N=CC=CC=1C(OCC)=O>>[N:23]1[CH:34]=[CH:43][CH:25]=[CH:26][C:31]=1[CH2:30][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[CH:15][C:16]4[O:17][CH2:18][CH2:19][O:20][C:21]=4[C:12]=3[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Br
Agent: BrCc1ccccn1
Agent: CCOC(=O)c1cccnc1CBr
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1c2ccc2c1OCCO2

Procedure:
Following the procedure as described in EXAMPLE 5.30 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-f][1,4]-benzodioxine-7,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace ethyl 2-(bromomethyl)nicotinate, (pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one was obtained (57%) as a colorless solid: mp 205-206° C.; 1H NMR (300 MHz, DMSO-d6) δ8.52 (d, 1H, J=4.7 Hz), 7.79 (ddd, J=7.7, 7.7, 1.7 Hz, 1H), 7.35-7.20 (m, 4H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.29 (ABq, 2H), 5.04 (ABq, 2H), 4.84 (ABq, 2H), 4.27 (s, 4H); 13C NMR (75 MHz, DMSO-d6) δ176.7, 155.2, 149.2, 148.8, 144.6, 142.5, 137.0, 131.6, 129.2, 128.6, 123.6, 122.9, 122.6, 122.4, 121.4, 114.4, 109.8, 109.2, 80.2, 64.1, 63.9, 57.3, 44.8; MS (ES+) m/z 387.7 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:14]([Cl:28])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+].Cl>O1CCCC1.O>[Cl:28][C:14]1[CH:13]=[N:12][C:11]2=[N:16][C:15]=1[NH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([O:27][CH2:2][CH2:3][C:4]3[CH:5]=[C:6]([NH:10]2)[CH:7]=[CH:8][CH:9]=3)[CH:24]=[CH:25][CH:26]=1
Reactant: Oc1cccc(CCCNc2nc(Nc3cccc(CCBr)c3)ncc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1cnc2nc1NCCCc1cccc(c1)OCCc1cccc(c1)N2
Yield: 10.9 %

Procedure:
To a solution of 3-{3-[(2-{[3-(2-bromoethyl)phenyl]amino}-5-chloropyrimidin-4-yl)amino]propyl}phenol (50.0 mg, 0.108 mmol) in tetrahydrofuran (1.0 mL) was added a solution of sodium hydroxide in water (1.0 mL, 1.0 M). The resultant solution was stirred at rt for 60 hours until the reaction was complete. The reaction mixture was neutralized with HCl (3 M aqueous solution) to pH=7. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude, which was purified by silica gel column chromatography to give the desired product as a white powder (4.5 mg, 11%). LCMS for C21H22ClN4O (M+H)+: m/z=381.0. 1H NMR (400 MHz, CD3OD): δ 7.98 (s, 1H), 7.92 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.40 (m, 1H), 7.06 (m, 1H), 6.97 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.62 (m, 2H), 3.60 (m, 4H), 3.20 (m, 2H), 2.68 (t, J=7.6 Hz, 2H), 2.02 (t, J=7.6 Hz, 2H).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[F:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][OH:34])=N)=[CH:29][CH:28]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:34][N:33]=[C:31]([C:30]4[CH:35]=[CH:36][C:27]([F:26])=[CH:28][CH:29]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1ccc(F)cc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccc(F)cc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 4-fluoro-N-hydroxy-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.87 min; Mass spectrum (ESI+): m/z=474 [M+H]+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li][CH2:12][CH2:13][CH2:14][CH3:15].[N:16]1[CH:21]=[CH:20][CH:19]=C[C:17]=1[C:22]([OH:24])=[O:23].C(=O)CC>C1COCC1>[CH2:14]([CH:13]1[C:12]2[C:17](=[N:16][CH:21]=[CH:20][CH:19]=2)[C:22](=[O:23])[O:24]1)[CH3:15]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccccn1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: C1CCOC1
Solvent: CCC=O
Product: CCC1OC(=O)c2ncccc21
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 11 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (20.3 ml, 120 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 60 ml of dry THF is added. The reaction mixture is cooled to −78° C. The cooled reaction mixture is treated dropwise with nBuLi solution (64 mL of a 2.5 M solution in hexanes, 160 mmol) and the reaction is let stir at −78° C. for 5 min. A solution of picolinic acid (4.92 g, 40 mmol) in THF (60 mL) is added dropwise to the reaction at −78° C. The reaction is stirred at −78° C. for 1 h and is then warmed to −20° C. for 30 min. The reaction mixture is treated with propionaldehyde (7.2 ml, 100 mmol, 2.5 eq) dropwise at −50° C. The reaction is stirred at −20° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated and the residue is dissolved in water and ether. The aqueous layer is collected and extracted with dichloromethane and ether (6×50 ml). The aqueous phase is concentrated and the residue is dissolved in EtOH (30 mL) and acetic acid (2 mL) and heated at reflux overnight under argon. The reaction mixture is cooled to room temperature and concentrated. The residue is purified by chromatography (silica gel) to give the title compound (0.70 g, 11%).
Reaction SMILES: [Mg].BrC(Br)C.[CH2:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15]Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[C:27](=O)([O:30]C)[O:28][CH3:29]>O1CCCC1>[CH2:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:15][C:27]([O:28][CH3:29])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC(CBr)CCCCCCCC
Reactant: COC(=O)OC
Agent: CC(Br)Br
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCC(CCCCCCCC)CC(=O)OC
Reaction time: 2 h
Yield: 66.5 %

Procedure:
3 g (123.3 mmol) of magnesium was suspended in 30 ml of a dehydrated tetrahydrofuran solution under nitrogen atmosphere to activate the magnesium with dibromoethane. 120 ml of a dehydrated tetrahydrofuran solution comprising 8.0 g (22.1 mmol) of the synthesized 2-octyl-1-bromododecane was added to this solution by dropping. After dropping, the solution was stirred for two hours. The reaction mixture was cooled with ice, 2.0 ml (23.7 mmol) of dimethyl carbonate was added, and the mixture was stirred overnight at room temperature (25° C.). After filtering the reaction solution, adding diluted hydrochloric acid to the filtrate, and extracting using hexane, the solvent was evaporated under reduced pressure. The residue was distilled under the conditions of 0.15 mmHg and an oil bath temperature of 180 to 190° C. to obtain 5.0 g (14.7 mmol) of methyl 3-octyl-tridecanoate as a colorless oil. The fluidity of this compound did not decrease even when cooled to −20° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([O:19]C)=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][C:32]=1[O:39][CH3:40]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([F:30])=[C:32]([O:39][CH3:40])[CH:33]=2)=[O:19])[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)nc(C)n1
Reactant: COc1cc(CN)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(CNC(=O)c2cc(CO[Si](C)(C)C(C)(C)C)nc(C)n2)ccc1F
Temperature: 70 °C
Yield: 81.2 %

Procedure:
To a stirred solution of methyl 6-((tert-butyldimethylsilyloxy)methyl)-2-methylpyrimidine-4-carboxylate (4.70 g, 15.86 mmol, Preparation #6) in MeOH (50 mL) were added DIEA (8.3 mL, 47.59 mmol Spectrochem) and 4-fluoro-3-methoxybenzylamine (3.8 g, 24.58 mmol, WO 2008/083056). The reaction mixture was heated to about 70° C. for about 15 h. The solvents were removed in vacuo and the crude material partitioned between EtOAc (300 mL) and 1N HCl solution (300 mL). The layers were separated and the aqueous layer extracted with EtOAc (1×150 mL). The combined organic layers were washed successively with 1N HCl solution (1×200 mL), water (1×200 mL) and brine (1×250 mL), dried over sodium sulphate and evaporated to dryness. The residue obtained was purified by silica gel (60-120 mesh) chromatography eluting with 25 to 35% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford 6-((tert-butyldimethylsilyloxy)methyl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide 5.4 g (81%); 1H NMR (400 MHz, DMSO): δ 9.431-9.400 (t, J=6.0 Hz, 1H), 7.884 (s, 1H), 7.173-7.112 (m, 2H), 6.897-6.860 (m, 1H), 4.794 (s, 2H), 4.468-4.452 (d, J=6.4 Hz, 2H), 3.814 (s, 3H), 2.68 (s, 3H), 0.934 (s, 9H), 0.118 (s, 6H), MS m/z: 420 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].[CH3:13]O>>[CH3:13][O:11][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:12]
Reactant: CO
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: COC(=O)c1cc2ccccc2[nH]1

Procedure:
50 g Indole-2-carboxylic acid were stirred with 400 ml methanol/10% H2SO4 for 48 hours. The resulting crystals were filtered off and washed with methanol giving 51.3 g product.
Reaction SMILES: [O:1]([CH:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>CCOCC>[O:1]([CH:8]1[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: O=C1CCC(Oc2ccccc2)CC1
Reaction time: 8 h

Procedure:
11.7 g (50 mmole) 8-phenoxy-1,4-dioxa-spiro[4.5]decane (25) were dissolved in 250 in ether. 50 ml water and 37.5 ml concentrated hydrochloric acid were added with stirring. The mixture was stirred for 2 hours and allowed to stand overnight. After subsequent phase separation the mixture was extracted with ether and washed with saturated common salt solution, and the solvent was distilled off. 9 g (91% theoretical) of compound (26) were obtained.
Reaction SMILES: C1([Mg]Br)C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][CH2:14][NH2:15].C[O:20][C:21](=O)[CH:22]([CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[CH2:24].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][N:15]2[C:21](=[O:20])[C:22]([CH:36]([CH3:37])[CH3:38])=[C:23]([CH3:24])[N:25]=[C:26]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:16]=[CH:17][CH:18]=1
Reactant: C=C(NC(=O)c1ccccc1OC)C(C(=O)OC)C(C)C
Reactant: NCCc1cccc(F)c1
Agent: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1nc(C)c(C(C)C)c(=O)n1CCc1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
Phenyl magnesium bromide (1M solution in THF, 0.0021 mol) was added to a solution of 3-fluoro-phenethyl amine (0.27 mL, 0.0021 mol) in anhydrous toluene (20 mL). After stirring the mixture at 20° C. for 10 min, 2-isopropyl-3-(2-methoxy-benzoylamino)-but-3-enoic acid methyl ester of step (b) above in this method (Method B of Example 13) (0.05 g, 0.0017 mol) was added. The mixture was refluxed for 10 hours, cooled and ethyl acetate (50 mL) was added followed by 1N HCl (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with 1N HCl (3×100 mL), water (100 mL), and brine (100 mL). After drying over sodium sulfate and concentration on a rotatory evaporator, the product was purified by column chromatography over silica gel (200-400 mesh) eluting with 12% EtOAc/hexanes to give 3-[2-(3-fluoro-phenyl)-ethyl]-5-isopropyl-2-(2-methoxy-phenyl)-6-methyl-3H-pyrimidin-4-one (0.3 g, 46%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:19].OS(O)(=O)=O.O=[Cr](=O)=O.OS(O)(=O)=O.O>CC(C)=O.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[C:15]([OH:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
600 mg of alcohol 165 (2.64 mmol) was dissolved in 15 ml of acetone, cooled to 0° C. and added dropwise with 5 ml of Jones reagent (7.40 mmol, 2.8 eq.) (freshly prepared from 2 g of CrO3, 2.7 g of conc. H2SO4, 12 ml of H2O) and stirred for 2 h at RT, the course of the reaction being monitored using TLC (EE/CH 1:1). This was followed by addition of 4 ml of isopropanol, during which the orange color of the reaction mixture gradually turned green-brown. Filtration over Celite was followed by washing with 5 ml of an acetone/glacial acetic acid mixture (20:1) and concentrating to dryness. The remaining greenish residue was purified using silica gel column chromatography (CH2Cl2/MeOH 20:1), thereby obtaining 470 mg of vinylproline 166 (1.95 mmol, 74%) in the form of white crystals suitable for X-ray crystallographic analysis.