Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH2:35])=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:2]3[N:24]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=5[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:32][CH:33]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1ccccc1CNc1cccn2nc(Nc3ccc4cnccc4c3)nc12)S(C)(=O)=O

Procedure:
N-(2-{[2-(Isoquinolin-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide was prepared from N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (100.0 mg, 0.2733 mmol) and isoquinolin-6-ylamine (45.0 mg, 0.312 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.079 g, 61%). 1H NMR (400 MHz, CDCl3, δ, ppm): 9.09 (s, 1H), 8.43 (d, J=5.1 Hz, 1H), 8.28 (s, 1H), 7.92-7.87 (m, 2H), 7.62 (d, J=5.3 Hz, 1H), 7.54 (d, J=6.8 Hz, 2H), 7.40-7.28 (m, 3H), 7.18 (s, 1H), 6.76 (t, J=7.0 Hz, 1H), 6.44 (d, J=7.3 Hz, 1H), 5.39-5.32 (m, 1H), 4.75 (d, J=5.4 Hz, 2H), 3.32 (s, 3H), 3.02 (s, 3H). MS=474 (MH)+.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[N+:10]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:24]([CH3:26])=O)[C:19](OCC)=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:24]([CH3:26])=[C:18]([CH2:17][C:16]3[CH:27]=[CH:28][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=3)[C:19](=[O:20])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(Cc2ccc([N+](=O)[O-])cc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol (0.48 g) and ethyl 2-(4-nitrobenzyl)acetoacetate (1.00 g) in ethanol (150 ml) was treated with dry HCl at 0° C. for 7.5 hours and the solution was kept at that temperature overnight. Solvent was evaporated and the precipitate triturated with water. Yield 0.63 g (51%). Melting point 280-285° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[NH4+].[Cl-]>C(Cl)Cl>[I:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]([S:20]([CH3:19])(=[O:22])=[O:21])[S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution containing 2-iodo-4-nitroaniline (25 g; 95 mmol) and triethylamine (43 ml; 312 mmol) in CH2Cl2 (250 ml), a solution containing methanesulphonyl chloride (36 g; 312 mmol) was added dropwise. The reaction mixture was left under stirring at room temperature for 18 hours, then NH4Cl (saturated solution) was added (250 ml). The biphasic solution was transferred into a separating funnel, the organic phase was separated, dried over Na2SO4 and the solvent was removed by evaporation under reduced pressure. The residue was suspended in EtOH (200 ml) and heated under stirring until a yellow solid precipitated. The crude product was filtered, washed with EtOH (750 ml), and dried under vacuum to give N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (32 g) which was used in the following reaction without any further purification.
Reaction SMILES: [Li+].[OH-].C([O:16][CH2:17][C:18]1[C:22]([OH:24])([CH3:23])[O:21][C:20](=[O:25])[C:19]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=O)CCCCCCCCCCC.C(O)(=O)C>C1COCC1>[OH:16][CH2:17][C:18]1[C:22]([OH:24])([CH3:23])[O:21][C:20](=[O:25])[C:19]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1(C)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(O)OC(=O)C(c2ccccc2)=C1CO
Reaction time: 3 h

Procedure:
LiOH (0.5M, 19.7 mL, 9.83 mmol) was added to a solution of 4-dodecoyloxymethyl-5-hydroxy-5-methyl-3-phenyl-2-furanone (Compound 5, see improved process for preparation below), in THF (20 mL) at room temperature. After stirring for 3 hours the reaction was quenched with glacial acetic acid (590 mg, 9.83 mmol) and the THF was removed by rotary evaporator. Solids were removed from the residual aqueous slurry. The clear aqueous solution containing the crude product was lyophylized, adhered to silica with methanol and purified by flash chromatography using 60% ethyl acetate/hexane to give the title alcohol.
Reaction SMILES: COCCOC.Br[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1B(O)O
Reactant: CCOC(=O)c1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1ncccc1-c1ccccc1CNC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
150 ml of 1,2-dimethoxyethane were aerated with argon, and 874 mg (0.75 mmol) of Pd(PPh3)4 and 3.45 g (15 mmol) ethyl 3-bromopyridine-2-carboxylate were added. After 10 min, 5.53 g (22.5 mmol) of 2-(tert-butoxycarbonylaminomethyl)phenylboronic acid and finally 15 ml of a 2M sodium carbonate solution were added. The mixture was heated to reflux for 18 h under argon, diluted with dichloromethane after cooling and washed with water. The organic phase was dried, concentrated and purified by chromatography on silica gel. 3.4 g (66%) of a viscous oil were obtained. MS (ES+): m/z=357 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][CH2:41][CH2:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:49]2[CH:50]=[CH:51][C:46]([S:43]([CH2:42][CH2:41][O:40][CH3:39])(=[O:44])=[O:45])=[CH:47][CH:48]=2)=[CH:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 55.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 122, 550 mg, 0.99 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (603 mg, 2.47 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.01 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.24 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (320 mg, 55%) as a white solid: LC/MS m/e calcd for C29H29FN2O6S2 [M+H]+ 585.69, observed 585.1.
Reaction SMILES: N1([C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3C=CC(C(OC)=O)=CC=3)=CC4)CC2)CC1.[CH3:43][C@:44]12[C@@:61]3([CH3:62])[C@@H:52]([C@:53]4([CH3:74])[C@@H:58]([CH2:59][CH2:60]3)[C:57]([CH3:64])([CH3:63])[C:56]([C:65]3[CH:73]=[CH:72][C:68]([C:69]([OH:71])=[O:70])=[CH:67][CH:66]=3)=[CH:55][CH2:54]4)[CH2:51][CH2:50][C@@H:49]1[C@H:48]1[C@H:75]([C:78]([CH3:80])=[CH2:79])[CH2:76][CH2:77][C@:47]1([NH:81][CH2:82][CH2:83][N:84]1[CH2:89][C@@H:88]3[CH2:90][C@@H:86]([N:87]3[S:91]([CH3:94])(=[O:93])=[O:92])[CH2:85]1)[CH2:46][CH2:45]2.C12C(NC(=O)OC(C)(C)C)C1CNC2>>[CH3:43][C@:44]12[C@@:61]3([CH3:62])[C@@H:52]([C@:53]4([CH3:74])[C@@H:58]([CH2:59][CH2:60]3)[C:57]([CH3:63])([CH3:64])[C:56]([C:65]3[CH:73]=[CH:72][C:68]([C:69]([OH:71])=[O:70])=[CH:67][CH:66]=3)=[CH:55][CH2:54]4)[CH2:51][CH2:50][C@@H:49]1[C@H:48]1[C@H:75]([C:78]([CH3:80])=[CH2:79])[CH2:76][CH2:77][C@:47]1([NH:81][CH2:82][CH2:83][N:84]1[CH2:85][CH:86]3[CH:90]([CH:88]3[NH:87][S:91]([CH3:94])(=[O:93])=[O:92])[CH2:89]1)[CH2:46][CH2:45]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@H]4C[C@@H](C3)N4S(C)(=O)=O)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
Agent: C=C(C)[C@@H]1CC[C@]2(N3CC3)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: CC(C)(C)OC(=O)NC1C2CNCC21
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CC4C(C3)C4NS(C)(=O)=O)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: 12 %

Procedure:
4-((1R,3 aS,5aR,5bR,7aR,11 aS,11bR,13 aR,13bR)-5a,5b,8,8,11a-Pentamethyl-3a-((2-(6-(methylsulfonamido)-3-azabicyclo[3.1.0]hexan-3-yl)ethyl)amino)-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 was prepared in 12% yield over three steps from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-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 method used in the preparation of 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-((1R,5S)-6-(methylsulfonyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)ethyl)amino)-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 in step 1 tert-butyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate was used instead of (1R,5S)-tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate. LC/MS: m/e 732.5 (M+H)+, 3.86 min (method 8). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 7.90 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.3 Hz, 2H), 5.28 (d, J=4.9 Hz, 1H), 5.23 (s, 1H), 5.13 (s, 1H), 4.85 (s, 1H), 4.72 (br. s., 1H), 3.85 (br. s., 2H), 3.72 (br. s., 2H), 3.48 (br. s., 4H), 3.09 (br. s., 1H), 3.03 (s, 3H), 2.81 (d, J=10.3 Hz, 1H), 2.25-1.97 (m, 8H), 1.87 (d, J=11.5 Hz, 1H), 1.79-1.60 (m, 6H), 1.53 (d, J=16.1 Hz, 6H), 1.44-1.33 (m, 4H), 1.30-1.23 (m, 2H), 1.21 (br. s., 3H), 1.11-1.04 (m, 3H), 1.02 (s, 3H), 0.94 (s, 3H), 0.93 (br. s., 3H).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:10][C:5]=2[S:4][C:3]=1[C:21]([NH2:23])=[O:22].C1CCN2C(=NCCC2)CC1.C(N)(=[S:37])C>CN(C=O)C.Cl>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([SH:37])=[C:3]([C:21]([NH2:23])=[O:22])[S:4][C:5]=2[CH:10]=1
Reactant: CC(N)=S
Reactant: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: NC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1S
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 21.6 %

Procedure:
To a mixture of 3-chloro-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxamide (193.6 mg) in DMF (dry) (2.5 mL) were added DBU (0.225 mL) and thioacetamide (113 mg). The mixture was stirred at 80° C. for 5.5 h. After cooling, the mixture was diluted with 1N HCl and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The precipitate was washed with hexane and THF to give the title compound (41.6 mg).
Reaction SMILES: B(O)O.Br[C:5]1[CH:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:5]1[CH:6]=[C:7]([CH:10]=[O:11])[S:8][CH:9]=1
Reactant: OB(O)c1ccco1
Reactant: O=Cc1cc(Br)cs1
Agent: OBO
Product: O=Cc1cc(-c2ccco2)cs1

Procedure:
4-(furan-2-yl)thiophene-2-carbaldehyde was prepared using the general boronic acid coupling procedure with 4-bromothiophene-2-carbaldehyde and furan-2-ylboronic acid (26 mg, 93 mg theoretical, 28.0%). LC-MS m/z 179 (M+1).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([S:12][CH3:13])[N:5]=1.[C:14]([O:19][CH3:20])(=[O:18])[CH:15]([CH3:17])[OH:16].CN(C)C=O>O>[CH3:11][O:10][C:8]1[N:7]=[C:6]([S:12][CH3:13])[N:5]=[C:4]([O:16][CH:15]([C:14]([O:19][CH3:20])=[O:18])[CH3:17])[CH:9]=1
Reactant: COc1cc(Cl)nc(SC)n1
Reactant: COC(=O)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(OC)nc(SC)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
0.4 g of sodium hydride was added to a mixture of 1.59 g of 4-chloro-6-methoxy-2-methylthiopyrimidine, 1.13 g of methyl lactate and 10 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 1.5 g of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylthiopyrimidine.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][C:20]([CH3:22])=[O:21])=[C:9]([O:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.S(Cl)([Cl:25])=O>CN(C)C=O>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][C:20]([CH3:22])=[O:21])=[C:9]([O:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC(=O)Oc1cc2ncnc(O)c2cc1OCC1CCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2ncnc(Cl)c2cc1OCC1CCCC1

Procedure:
3.80 g of 4-hydroxy-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline are suspended in 90 ml thionyl chloride and heated to boiling under a nitrogen atmosphere. After the addition of four drops of N,N-dimethylformamide the reaction mixture is refluxed for a further two hours. After cooling to ambient temperature the excess thionyl chloride is distilled off in a water jet vacuum. The brown residue is stirred with 30 ml toluene. The solvent is distilled off, leaving 4.30 g of a greyish-brown solid, which is reacted further without any more purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[CH:22][C:23]=2[C:24](=[O:34])[NH:25][C:26]2([C:32]#[N:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.CS(O)(=O)=[O:37].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:32]([C:26]1([NH:25][C:24]([C:23]2[CH:22]=[N:21][N:12]3[C:13]([C:14]4[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=4)=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:9]=[N:10][C:11]=23)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)(=[O:37])[NH2:33]
Reactant: CS(=O)(=O)O
Reactant: N#CC1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: NC(=O)C1(NC(=O)c2cnn3c(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)cnc23)CCCCC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
To a solution of the compound obtained in Example A1 (70 mg) in methylene chloride (1.0 mL) were added methanesulfonic acid (84 μL) and a few drops of water, and the mixture was stirred at room temperature overnight and at 35° C. for 4 hours. To the reaction mixture was added successively an aqueous saturated sodium hydrogencarbonate solution and methylene chloride. After stirring, the organic layer was separated and concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (solvent; chloroform/methanol=100/0 to 95/5) to give 3-[N-(1-carbamoylcyclohexyl)carbamoyl]-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (18 mg; yield: 25%) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.Cl[C:18]1[S:19][CH:20]=[CH:21][N:22]=1>>[O:3]=[C:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH:9]1[C:18]1[S:19][CH:20]=[CH:21][N:22]=1
Reactant: Clc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(=O)C(c2nccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
Add sodium hydride (3.61 g, 90.3 mmol) to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (12.0 g, 60.2 mmol) and stir for one hour at ambient temperature. Add 2-chlorothiazole (7.92 g, 66.3 mmol) and stir one additional hour at ambient temperature. Heat to reflux and stir for 14 hours at reflux. Cool mixture to ambient temperature and quench with sufficient HCl (2N) to adjust the pH of the mixture to less than 5. Extract the mixture three times with EtOAc; combine the organic extracts; sequentially wash with water then brine; dry over magnesium sulphate; filter; collect the filtrate; and then concentrate under vacuum at 40° C. Purify the crude material by silica gel flash column chromatography eluting with 10% EtOAc in hexane to give the title compound as a white solid (4.0 g, 23.5%). 1HNMR (d6-DMSO) δ 1.3 (s, 9H), 2.3-2.5 (m, 2H), 3.5 (t, J=6.1 Hz, 2H), 4.1-4.3 (m, 3H), 7.5 (s, 1H), 7.7 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:6]([CH:8]([CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.C([O-])(=O)C.[NH4+:33].C(O)(=O)C>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[N:33]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CCOC(=O)C(CCC(=O)c1ccccc1)C(=O)c1ccc(OC)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccc(OC)c(OC)c1
Yield: 62 %

Procedure:
A mixture of ethyl 2-(3,4-dimethoxybenzoyl)-5-oxo-5-phenylvalerate (compound no. 314; 7.7 g; 0.02 mole), ammonium acetate (3.1 g; 0.04 mole) and acetic acid (30 ml) is heated to reflux temperature for 4 hours. The reaction medium is poured into water (300 ml): an oil in released. The latter is extracted with ethyl acetate (200 ml). The organic solution is washed with water (3×100 ml), then dried over anhydrous magnesium sulphate and concentrated under reduced pressure. A light brown oil (4.5 g; yield: 62%) is obtained which corresponds to ethyl 2-(3,4-dimethoxyphenyl)-6-phenylnicotinate.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:7](=[NH:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:26][C:27]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C1COCC1>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)/[C:7](=[N:18]/[C:29](=[O:30])[C:28]2[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:27]=2[F:26])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: Cn1c(C(C)(C)C)cc(=N)n1CC1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2F)n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.4 %

Procedure:
To a solution of Example 95E (0.53 g, 2.1 mmol) and Et3N (0.88 mL, 6.3 mmol) in THF (10 mL) was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.320 mL, 2.108 mmol). The mixture was stirred at ambient temperature for 4 h then was quenched with saturated aqueous NaHCO3 (10 mL) and diluted with EtOAc (10 mL). The layers were separated and the aqueous phase was extracted EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 50% hexanes in EtOAc) afforded the title compound (0.48 g, 1.1 mmol, 52% yield). MS (DCI/NH3) m/z 442 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[NH:4][CH2:3]1.CC1N([C:26]([CH2:28][C:29]#[N:30])=[O:27])N=C(C)C=1.O1CCOCC1.C(=O)(O)[O-].[Na+]>O>[CH3:1][CH:2]1[C:5]2([CH2:10][CH2:9][CH2:8][N:7]([C:11]3[C:12]4[CH:19]=[CH:18][NH:17][C:13]=4[N:14]=[CH:15][N:16]=3)[CH2:6]2)[N:4]([C:26](=[O:27])[CH2:28][C:29]#[N:30])[CH2:3]1
Reactant: CC1CNC12CCCN(c1ncnc3[nH]ccc13)C2
Reactant: Cc1cc(C)n(C(=O)CC#N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1CN(C(=O)CC#N)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 21.3 %

Procedure:
An optically-active compound of 4-(3-methyl-1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine (25 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (32 mg) and 1,4-dioxane (750 μl), and the mixture was stirred at 100° C. for 3.5 hours. The mixture was cooled to room temperature. Thereto were added water and saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted with ethyl acetate five times, and the combined organic layer was washed with water and concentrated under reduced pressure. The resulting residue was purified by silica-gel thin layer chromatography (eluent: chloroform/methanol=9/1). The resulting residue was purified by silica-gel thin layer chromatography (eluent: ethyl acetate/methanol=93/7) again. The resulting solid (8.0 mg) was slurry-washed with n-hexane/ethyl acetate solution to give the titled compound (6.7 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:5]([CH:6]=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[C:8]([O:10][CH3:11])[C:5]=1[CH2:6][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(O)cc(OC)c1C=O
Reactant: C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(O)cc(OC)c1CN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (0.30 g, 1.65 mmol), piperidine (0.20 mL, 1.98 mmol) and acetic acid (0.47 mL, 8.25 mmol) in methanol (20 mL) was stirred for 20 minutes before addition of sodium cyanoborohydride (0.27 g, 4.30 mmol). The reaction mixture was allowed to stir at ambient temperature for 4 h then loaded onto a 10 g SCX-2 cartridge which was then washed with methanol (30 mL) and then eluted with 2N ammonia in methanol (50 mL). Concentration of the combined basic fractions in vacuo afforded the title compound (220 mg, 53%) as a white solid. 1H NMR (DMSO-D6, 300 MHz): 9.39 (s, 1H), 6.03 (s, 2H), 3.66 (s, 6H), 3.30 (s, 2H), 2.32-2.24 (m, 4H), 1.42-1.35 (m, 4H), 1.34-1.26 (m, 2H). LCMS (Method B): RT=1.90 min, M+H+=252.