Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[Li]CCCC.CON(C)[C:26]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[N:31]2)=[O:27]>C1COCC1>[F:1][C:2]1[C:7]([C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][CH:32]=[N:31]3)=[O:27])=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1F
Reactant: CON(C)C(=O)c1ccc2nccnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3nccnc3c2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
To a solution of tert-butyl (2,4,5-trifluorophenyl)carbamate (2.72 g, 11 mmol, 1.1 eq.) in THF (150 mL) cooled at −78° C. was added n-BuLi (9.17 mL, 22 mmol, 2.2 eq.) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of N-methoxy-N-methylquinoxaline-6-carboxamide (2.17 g, 10 mmol, 1.0 eq.) in THF (50 mL) was added dropwise. The resulting mixture was stirred at −78° C. for 1 h, then quenched by the addition of NH4Cl solution. The mixture was extracted with EA (100 mL×3). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford tert-butyl (2,4,5-trifluoro-3-(quinoxaline-6-carbonyl)phenyl)carbamate as yellow foam (600 mg, 14.9%)
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([CH3:11])(=[O:10])=[O:9].Cl>N1C=CC=CC=1>[OH:1][C@H:2]([CH2:6][O:7][S:8]([CH3:11])(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: N#CC[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@@H](O)CC#N

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (8.0 g, 79.1 mmol), pyridine (19.1 ml) and mesyl chloride (7.33 ml) were mixed at 0° C. for 6 hours. The mixture was poured in ice-cooled 1N hydrochloric acid and stirred, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off with an evaporator. The residue was purified with silica gel column chromatography (acetone:chloroform=5:95) to obtain (3S)-3-hydroxy-4-methanesulfonyloxybutyronitrile (8.1 g). Yield, 57 %.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>C1(C)C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH:37][C:14](=[O:16])[C:13]3[CH:12]=[CH:11][C:10]([CH:7]4[CH2:6][CH2:5][N:4]([CH2:1][CH:2]=[CH2:3])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: C=CCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: C=CCN1CCC(c2ccc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cc2)CC1
Yield: 38.3 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-(1-prop-2-enylpiperidin-4-yl)benzamide was prepared following the procedure as outlined for Example 99, starting from methyl 4-(1-prop-2-enylpiperidin-4-yl)benzoate (0.259 g, 1.00 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) and 2M trimethylaluminium (1.250 mL, 2.50 mmol) in toluene (10 ml). The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2.5M ammonia/methanol in DCM. Pure fractions were evaporated to dryness and the product was crystallised from DCM/diethyl ether to give on filtration the title compound (0.182 g, 38.3%) as a white solid.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:13](Cl)(=[O:16])[CH2:14][CH3:15]>C(N(CC)CC)C>[C:1]1([CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)Cl
Reactant: Cc1ccccc1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC(=O)Oc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
At 0° C., to a mixture of o-cresol 10 g and chloroform 100 ml was added propionyl chloride 10 g and triethylamine 28 g. The resulting mixture was raised to room temperature and was stirred for two hours. Then the reaction mixture was extracted with chloroform and the organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give propionic acid o-tolyl ester 14 g.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(O)C.C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([N:20]1[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]1)[CH2:2]2
Reactant: O=C1CC2CCN1CC2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C2CN3CCC2CC3)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
1 g (8 mM) of quinuclidinone, 1.63 g (8.75 mM) of 1-piperazinecarboxylic acid t-butyl ester (1-Boc-piperazine) and 2.71 ml (9.1 mM) of titanium isopropoxide are mixed and this mixture is kept under agitation for 1 hour. 5 ml of ethanol and then 460 mg (7.3 mM) of sodium cyanoborohydride are then added, and this mixture is agitated for 24 hours at ambient temperature. 25 ml of water are added and agitation is carried out for 15 minutes. The precipitate formed is separated off by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by NH2 silica gel chromatography in eluting with the aid of a toluene/isopropanol mixture (95/5; v/v). 1 g of the compound sought after are thus obtained as a white solid (yield=42%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56](O)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.[CH:75]12[NH:82][CH:79]([CH2:80][CH2:81]1)[CH2:78][O:77][CH2:76]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:71])[CH3:72])(=[O:68])=[O:69])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:51][CH2:52]5)[N:48]=[C:47]([CH:53]([CH3:54])[CH3:55])[C:46]=4[C:56]([N:82]4[CH:75]5[CH2:81][CH2:80][CH:79]4[CH2:78][O:77][CH2:76]5)=[O:57])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reactant: C1CC2COCC1N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C4CCC3COC4)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 33.3 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (34 mg, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/MeOH gradient, and concentrated to give the titled compound (30 mg, 0.038 mmol, 34% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[NH:3]1.[I:16]Cl>C(O)(=O)C>[I:16][C:13]1[CH:14]=[CH:15][C:4]2[NH:3][C:2](=[O:1])[N:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]=2[CH:12]=1
Reactant: ClI
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)n1c(=O)[nH]c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 9.00 g (43.6 mmol) of ethyl 2-oxo-2,3-dihydrobenzimidazole-1-carboxylate (IV) and 14.2 g (87.3 mmol) of iodine monochloride in acetic acid (100 ml) was stirred at room temperature for 5 min and then at 85° C. for 2.5 h. The cooled reaction mixture was poured into ice-water. The precipitated solid was filtered off, washed with water, dried in vacuo and recrystallized from THF.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]2[NH:7][C:6]3[CH2:19][CH:20]4[NH:24][CH:23]([C:5]=3[C:4]=2[C:3]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]4.[H-].[Na+].I[CH3:35]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2[N:7]([CH3:35])[C:6]3[CH2:19][CH:20]4[NH:24][CH:23]([C:5]=3[C:4]=2[C:3]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]4
Reactant: CI
Reactant: CC(C)(C)OC(=O)c1c(Br)cc(OCc2ccccc2)c2[nH]c3c(c12)C1CCC(C3)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)cc(OCc4ccccc4)c31)C1CCC(C2)N1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of the product of step E (412 mg, 0.85 mmol) in DMF (10 mL) under a nitrogen atmosphere was added sodium hydride (60% dispersion in mineral oil, 69 mg, 1.70 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 1 h before addition of iodomethane (181 mg, 1.28 mmol). After stirring for an additional 2 h, the reaction mixture was quenched with water (50 mL) and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give tert-butyl 2-bromo-4-benzyloxy-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (420 mg, 99%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 7.31-7.50 (m, 5H), 7.21-7.27 (m, 1H), 6.75 (d, J=1.2 Hz, 1H), 5.05-5.23 (m, 3H), 4.67 (br s, 1H), 3.79 (s, 3H), 3.32 (br s, 1H), 2.42 (d, J=15.9 Hz, 1H), 2.21-2.36 (m, 1H), 2.07-2.21 (m, 1H), 1.85-1.96 (m, 1H), 1.55-1.65 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[C:31](OC)=[O:32].[O-]CC.[Na+]>C(O)C>[OH:32][C:31]1[C:19]2[CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][C:18]=2[N:15]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:16]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 110 °C
Yield: 55.8 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (1.8 g, 8.36 mmol, example 9e), 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (2.151 g, 8.36 mmol) and sodium ethoxide (0.569 g, 8.36 mmol) in ethanol (10 mL) were charged in a thick glass vial, which was sealed and heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and concentrated under reduced pressure yielding tert-butyl 4-hydroxy-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.970 g, 55.8%). The product was used as such in the subsequent step. MS (ES+) m/z 423.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[N:21]=2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH:7]=1>Cl.O1CCOCC1>[ClH:1].[ClH:1].[NH2:10][CH:8]([C:6]1[C:5]([O:18][CH3:19])=[C:4]([C:20]2[N:21]=[C:22]([C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[CH:23]=[CH:24][CH:25]=2)[C:3]([CH3:31])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cccc(C(=O)N(C)C)n1
Reaction time: 1 h

Procedure:
The tert-butyl [1-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-2-yl}-2-methoxy-4-methylphenyl)ethyl]carbamate (0.06 gm, 0.13 mmol) was dissolved in 4 M HCl in dioxane (3 mL) and was stirred for 1 hour. The reaction was complete and the mixture was concentrated in vacuo to give the crude product as an oil. LCMS calculated for C18H23ClN3O2(M+H)+: m/z=348.1. found: 348.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:12]=[CH:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C1C(=O)N([Cl:46])C(=O)C1.CO>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([Cl:46])=[C:11]([N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]2)[CH:10]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(N2CCN(C(=O)OC(C)(C)C)CC2)cc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
To a solution of tert-butyl 4-(3-(tert-butoxycarbonylamino)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (360 mg, 0.827 mmol) in DCM (4 mL) at −78° C. was added TFA (0.064 mL, 0.827 mmol). The reaction mixture was warmed to 0° C., followed by the addition of NCS (110 mg, 0.827 mmol) and MeOH (2.000 mL). The resulted reaction mixture was stirred at RT for 16 hours. The product was purified by flash chromatography (2% EtOAc/DCM, Rf 0.50) to give 150 mg (77% yield) of tert-Butyl 4-(5-(tert-butoxycarbonylamino)-2-chloro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate. 1H-NMR (CDCl3, 400 MHz): δ 10.31 (1H, s), 8.18 (1H, s), 7.98 (1H, s), 3.90 (3H, s), 3.61 (4H, t, J=4.8 Hz), 3.14 (4H, t, J=4.8 Hz), 1.53 (9H, s), 1.49 (9H, s).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]2([NH:20]C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[NH2:35][C:36]1[C:45]([F:46])=[C:44](F)[C:43](C)=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52].CS(C)=O>C(O)C.[C].[Pd]>[NH2:35][C:36]1[C:45]([F:46])=[C:9]([N:11]2[CH2:15][C@H:14]([CH3:16])[C@@H:13]([C:17]3([NH2:20])[CH2:18][CH2:19]3)[CH2:12]2)[C:43]([CH3:44])=[C:42]2[C:37]=1[C:38](=[O:56])[C:39]([C:53]([OH:55])=[O:54])=[CH:40][N:41]2[C@@H:49]1[CH2:51][C@@H:50]1[F:52]
Reactant: C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1c(N2C[C@H](C)[C@@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 150 °C
Reaction time: 18 h
Yield: 4.4 %

Procedure:
(3R,4R)-1-Benzyloxycarbonyl-3-(1-tert-butoxycarbonylaminocyclopropyl)-4-methylpyrrolidine (793 mg, 2.12 mmol) was dissolved in ethanol (50 ml), and the solution was mixed with 5% palladium-carbon (790 mg) to carry out hydrogenation under a pressure of 5 atmospheres. After completing the reaction, the 5% palladium carbon was removed by filtration and ethanol was evaporated. The thus obtained residue was dissolved in dimethyl sulfoxide (8 ml), and the solution was mixed with triethylamine (2 ml) and 5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl)-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (330 mg, 1.06 mmol) and stirred at 150° C. for 18 hours. After completing the reaction, dimethyl sulfoxide was evaporated, and the thus obtained residue was mixed with chloroform (100 ml) and washed with 10% citric acid (100 ml) and saturated brine (100 ml) in that order. The organic layer was dried over anhydrous sodium sulfate and then the solvent was evaporated. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After completing the reaction, the reaction solution was washed with dichloromethane (20 ml). The aqueous layer was adjusted to pH 12 with a sodium hydroxide aqueous solution and then to pH 7.4 with hydrochloric acid, subsequently carrying out extraction with chloroform (100 ml×4). The organic layers were combined and dried over anhydrous sodium sulfate and then the solvent was evaporated. The thus obtained residue was subjected to silica gel thin layer chromatography and developed with the bottom layer of a mixture solvent of chloroform:methanol=3:1, and then the resulting silica gel was scratched off and extracted with the same solvent system. The solvent was evaporated and the thus obtained residue was dissolved in a 1 N hydrochloric acid aqueous solution (6 ml) and stirred at room temperature for 10 minutes. After evaporating the solvent, the resulting crude product was recrystallized from isopropyl alcohol to obtain 20.1 mg (4%) of the title compound.
Reaction SMILES: Cl.Cl.[CH2:3]1[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][O:4]1.[Cl:13][C:14]1[C:19]([F:20])=[C:18](Cl)[N:17]=[C:16]([CH3:22])[N:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:13][C:14]1[N:15]=[C:16]([CH3:22])[N:17]=[C:18]([N:10]2[CH2:11][CH2:12][N:7]3[C@H:8]([CH2:3][O:4][CH2:5][CH2:6]3)[CH2:9]2)[C:19]=1[F:20]
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: C1CN2CCOC[C@@H]2CN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Cl)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Reaction time: 2 h

Procedure:
To a mixture of (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (23.28 g, 108.2 mmol) in DCM (360 mL) was added 4,6-dichloro-5-fluoro-2-methylpyrimidine (19.59 g, 108.2 mmol) and N,N-diisopropylethylamine (68 mL, 390.4 mmol). The mixture was stirred for 2 h, and the resulting solution was diluted with DCM (100 mL) and washed with saturated aq. NaHCO3 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHCO3 (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (9aS)-8-(6-chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine as a light yellow oil that was used without further purification. LCMS: (M+H)+: 287.1.
Reaction SMILES: [Li+].[Cl-].[CH3:3][N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH3:14])[CH:9]=[N:8][C:7]=2[N:6]([CH3:15])[C:5]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:9]2[N:10]([CH3:14])[C:11]3[C:12](=[O:13])[N:4]([CH3:3])[C:5](=[O:16])[N:6]([CH3:15])[C:7]=3[N:8]=2)=[CH:20][CH:19]=1
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: Clc1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(nc(-c3ccc(Cl)cc3)n2C)n(C)c1=O
Yield: 74.2 %

Procedure:
TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) was added to a solution of 1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (12) (194 mg, 1.0 mmol) in THF (2 mL) at 25° C. and the reaction mixture was then stirred at this temperature for max. 5 min. Pd(dba)2 (17 mg, 3 mol %) and P(o-furyl)3 (14 mg, 6 mol %) dissolved in THF (2 mL), and mixed with 1-chloro-4-iodobenzene (310 mg, 1.3 mmol, 1.3 equiv) were then transferred via cannula to the reaction mixture. The resulting mixture was stirred for 1 h at 25° C. The reaction mixture was then quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/ether, 1:1) furnished compound 14a (226 mg, 74%) as a colourless solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:30])[C:24]=2[CH:23]=[N:22]1>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:30][C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[N:22][NH:21]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc2[nH]ncc12
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Solvent: ClCCl
Product: O=C(Nc1cccc2[nH]ncc12)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 110 mg; 0.40 mmol) in DCM was treated with polymer-supported Mukaiyama reagent (1.1 g) followed by 1H-indazol-4-amine (Key Organics, 58.6 mg; 0.44 mmol). After stirring at RT for 72 hours the mixture was filtered and washed with saturated sodium bicarbonate solution. The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:34])=[C:24]([N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:34][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: C#CCN(c1cc(C(=O)C=CN(C)C)ccc1F)S(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCN(c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F)S(C)(=O)=O
Yield: 61.3 %

Procedure:
A mixture of 0.108 g (0.56 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.198 g (0.61 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-prop-2-ynyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 2 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 156 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-prop-2-ynyl-methanesulfonamide as a solid (yield 61%).