Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[C:17](C4C=NNC=4C#N)=[CH:18][N:19]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC(=O)N(C1C=CC(N2CCOCC2)=CC=1)C1C2N(C=CN=2)C([Sn](CCCC)(CCCC)CCCC)=CN=1)(C)(C)C.Br[C:73]1[O:81][CH:76]2[CH2:77][NH:78][C:79](=[O:80])[CH:75]2[CH:74]=1>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>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[C:15]4[N:16]([CH:27]=[CH:28][N:29]=4)[C:17]([C:73]4[O:81][C:76]5[CH2:77][NH:78][C:79](=[O:80])[C:75]=5[CH:74]=4)=[CH:18][N:19]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#Cc1[nH]ncc1-c1cnc(Nc2ccc(N3CCOCC3)cc2)c2nccn12
Reactant: O=C1NCC2OC(Br)=CC12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2nccn12
Solvent: CN(C)C=O
Product: O=C1NCc2oc(-c3cnc(Nc4ccc(N5CCOCC5)cc4)c4nccn34)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
In the same way as described for Compound 212, step 3 using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-imidazo[1,2-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (255 mg, 0.373 mmol), 2-bromo-3a,5,6,6a-tetrahydro-furo[2,3-c]pyrrol-4-one (50 mg, 0.249 mmol) and Pd(PPh3)4 (29 mg, 0.0249 mmol) in DMF (3 mL). The reaction mixture is concentrated in vacuo and the residue dissolved in 1:1 DCM:TFA (drop of H2O) and stirred at room temperature for 3 hours. The mixture is partitioned between ethyl acetate and sat. NaHCO3 and the aqueous layer is extracted with ethyl acetate (3×). The organic layers are combined, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with DCM followed by a 97:3 mixture DCM:NH3 (7M in MeOH). The fractions containing the desired compound are concentrated in vacuo to give a solid which is triturated with diethyl ether to afford the title compound (66.3 mg, 64%). Conversion of the compound into the mesylate salt using 1M MsOH (0.16 mL) affords the title product as a solid (69.3 mg, 87%). LCMS: Rt 2.52 min (99%), m/z (APCI) 417 (M+H)+, 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.36 (3H, s, MsOH), 3.25 (4H, m), 3.84 (4H, m), 4.52 (2H, s), 7.18 (2H, br s), 7.40 (1H, s), 7.83 (1H, s), 7.90 (3H, m), 8.21 (1H, br s), 8.44 (1H, s), 10.25 (1H, br s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C>[Br:8][C:6]1[CH:7]=[C:2]([Br:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(Br)cc(Br)cc1I
Reactant: C#Cc1ccc(OC)cc1
Solvent: O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3cc(Br)cc(Br)c3o2)cc1
Reaction time: 1 h

Procedure:
A solution of 2,4-Dibromo-6-iodo-phenol [53872-06-3] (0.7 g, 1.8 mmol), 4-Methoxyphenylacetylene (0.53 g, 4.0 mmol), PdCl2P(PH3)2 (70 mg), and Cul (50 mg) in DMF/Diethylamine (10 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic bayer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH and filtered to give 87 as a solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:30]=[C:29]([C:31]2S[C:33]3[CH2:39][CH2:38][CH2:37][CH2:36][C:34]=3[N:35]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3].[OH-:40].[Li+]>C1COCC1.O.CO>[CH2:1]([O:4][C:5]1[CH:30]=[C:29]([C:31]2[O:40][C:33]3[CH2:39][CH2:38][CH2:37][CH2:36][C:34]=3[N:35]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C@H:17]([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:15]2)[CH2:2][CH3:3]
Reactant: CCCOc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCOc1cc(-c2nc3c(o2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[2-propoxy-4-(4,5,6,7-tetrahydro-1,3-benzthiazol-2-yl)phenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 166, 88.0 mg, 0.160 mmol) in THF/Water/Methanol (1:2:1) was added solid lithium hydroxide (38.4 mg, 1.60 mmol). The solution was stirred at rt for 3 h, and the solvent was then removed under reduced pressure. The residue was diluted with water and acidified using HCl (2 N aqueous solution) upon which a white precipitate formed. The solid was isolated by filtration to provide the title compound (43.5 mg, 52%) that did not require further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, 1H), 7.32 (dd, 1H), 7.07 (d, 1H), 7.04 (d, 1H), 6.78 (s, 1H), 6.69 (dd, 1H), 4.15 (t, 2H), 4.11 (t, 2H), 3.96 (t, 2H), 3.33 (m, 1H), 2.61-2.85 (m, 7H), 2.2-2.30 (m, 3H), 2.11-2.19 (m, 2H), 1.58-1.84 (m, 7H), 0.98 (t, 3H); LC-MS: RT3.80 min, (M+H)+ 22.3.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH:4]=[C:5]([CH3:8])[CH:6]=[CH2:7].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I-].[PH4+]>C1C=CC=CC=1>[I-:1].[CH3:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CC(C)=CCCI
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [PH4+]
Solvent: c1ccccc1
Product: C=CC(C)=CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 89.0 g. (0.40 mole) of iodo-4-methyl-3,5-hexadiene, 105 g. (0.40 mole) of triphenylphosphine and 350 ml. of benzene was stirred and refluxed for 8 hours. The solvent was removed in vacuo. After addition of about 1 1. of ether the oily mixture was left for one day at 0°. The crystallized salt was suction filtered, finely grinded and washed with ether, then dried for 4 hours at 80°/0.01 Torr. Obtained: 140 g. of phosphonium iodide, m.p. 124°-128°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH:37]3[CH2:39][CH2:38]3)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:37]1([C:32]2[CH:31]=[C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:40])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)[CH:35]=[C:34]([CH3:36])[N:33]=2)[CH2:38][CH2:39]1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(C2CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C2CC2)n1

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopropyl-6-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M237) (273 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (177 mg, 82%).
Reaction SMILES: [O:1]=[O+][O-].[C:4]1([CH:10]([O:17][C:18](=[O:50])[CH:19]([N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:24]2=[O:49])[C:20](=C)[CH3:21])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(OCC)(=O)C>[C:11]1([CH:10]([O:17][C:18](=[O:50])/[C:19](/[N:23]2[CH:26]([S:27][S:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH:25]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:24]2=[O:49])=[C:20](\[OH:1])/[CH3:21])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Product: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 equivalent of ozone (diluted with oxygen) is passed into a solution, cooled to -70° C., of 681 mg (1.0 mM) of 2-[4-(benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 30 ml of ethyl acetate. The reaction solution is allowed to warm up, concentrated to 10 ml in vacuo, mixed with 1.0 ml of dimethyl sulphide and stirred for 15 hours at room temperature. Solvent and excess reagent are removed in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel, using toluene/ethyl acetate, 4:1 (15 ml fractions). 2-[4-(Benzthiazol-2-yldithio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester is obtained as a solid amorphous substance. [α]D =130°±1° (CHCl3 ; c=0.8) IR spectrum (CH2Cl2): 2.95, 5.60, 5.92, 6.04 and 8.10μ.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Li])CCC.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]=[O:25])=[CH:23][C:18]=2[O:17][CH2:16]1.C(O)(C)C>C1COCC1.O>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([CH:24]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[OH:25])=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1cccc(C(O)c2ccc3c(c2)OCO3)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A stirred mixture of 1-bromo-3-methoxy-benzene (1.49 g, 8.0 mmol) and dry THF (20 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (3.0 mL, 7.6 mmol) and stirred for 20 min. Then a mixture of benzo[1,3]dioxole-5-carbaldehyde (1.03 g, 6.8 mmol) in dry THF (15 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (3.5 mL, 46 mmol) and added water (10 mL). The mixture was extracted with EtOAc (3×40 mL). The combined organic phases were washed with water (2×40 mL), dried over MgSO4 and concentrated to give benzo[1,3]dioxol-5-yl-(3-methoxy-phenyl)-methanol as an oil (2.23 g, 113% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=4[Cl:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To a solution of 414.5 mg of 2,5-dichlorobenzoyl chloride in 5 ml of methylene chloride is added 276 μl of triethylamine. After stirring at 0° C. for 3 minutes 400 mg of the 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added. The bath is removed and the reaction mixture stirred at room temperature for 3 hours. The volatiles are concentrated in vacuo to give a residue which is dissolved in ethyl acetate and washed with water, 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried with Na2SO4 and concentrated in vacuo to a residue which is purified by thick layer chromatography by elution with 1:1 ethyl acetate-hexanes to give a residue. The residue is crystallized from ethyl acetate to give 220 mg of the desired product as white crystals, m.p. 218°-220° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:33])[C@@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10]1)(C)(C)C.Cl>C(O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:18]1([CH2:17][C@H:16]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)[C:15]([NH:14][C:11]2[CH:12]=[CH:13][N:9]([CH2:8][CH2:7][OH:6])[N:10]=2)=[O:33])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCO)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 787.2 %

Procedure:
N-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (135 mg, 0.26 mmol) was dissolved in ethanol (5 mL) and concentrated aqueous hydrochloric acid (100 μL) was added. The reaction stirred at 25° C. for 90 min. The reaction was diluted with ethyl acetate (50 mL), washed with water (20 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate and concentrated in vacuo to give a beige foam. The foam was dissolved in methylene chloride (4 mL) and hexanes (4 mL) were added to crystallize the desired product. Collection by filtration followed by rinsing with excess hexanes afforded 3-cyclopentyl-N-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-(R)-(4-methanesulfonyl-phenyl)-propionamide (830 mg, 78%) as colorless crystals: ESI-LRMS m/e calcd for C20H27N3O4S [M+] 405.17, found 406.35 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.21 (m, 2H, CH2), 1.38-1.82 (m, 8H, 4×CH2), 2.01-2.23 (m, 1H, CH), 3.17 (s, 3H, SO2CH3), 3.66 (q, J=5.5 Hz, 2H, OCH2), 3.89-3.95 (m, 1H, CH), 3.98 (t, J=5.5 Hz, 2H, NCH2), 4.80 (t, J=5.5 Hz, 1H, OH), 6.40 (d, Jo=2.2 Hz, 1H, Ar), 7.51 (d, Jo=2.2 Hz, 1H, Ar), 7.62 (d, Jo=8.5 Hz, 2H, Ar), 7.85 (d, Jo=8.5 Hz, 2H, Ar), 10.70 (s, 1H, NH).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)[CH3:2].C(OC)(=O)[CH2:15][C:16](OC)=[O:17].C[O-].[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][C:11](=[O:13])[CH:12]=[C:16]([OH:17])[CH2:15]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C=CC(C)=O)cc1
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(C2CC(=O)C=C(O)C2)cc1
Temperature: 25 °C

Procedure:
144 g (0.83 mol) of 4-(4-ethylphenyl)-3-buten-2-one dissolved in a small amount of methanol is dripped into 109 g (0.83 mol) of dimethyl malonate and 45 g (0.83 mol) of sodium methylate in 40 ml of methanol. The mixture is stirred at reflux for 3 hours and for 10 hours at room temperature. The methanol is distilled off, and the residue is taken up in 2 liters of 10% strength potassium hydroxide solution and stirred for 8 hours at room temperature. At 60° C., the mixture is acidified to pH 1 with concentrated hydrochloric acid. The mixture is stirred for a further 2 hours and suction filtered, and the precipitate is dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]([C@@H:19]3[CH2:23][C@@H:22]([O:24][CH3:25])[CH2:21][NH:20]3)[N:13]([CH3:18])[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.[CH2:28]([N:30](CC)[CH2:31]C)C.Cl[C:36](=[O:41])[C:37](OC)=[O:38].CNC.C1COCC1>>[CH3:28][N:30]([C:36](=[O:41])[C:37]([N:20]1[CH2:21][C@H:22]([O:24][CH3:25])[CH2:23][C@H:19]1[C:12]1[N:13]([CH3:18])[C:14](=[O:17])[C:15]([OH:16])=[C:10]([C:8]([NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:27][CH:26]=2)=[O:9])[N:11]=1)=[O:38])[CH3:31]
Reactant: CCN(CC)CC
Reactant: COC(=O)C(=O)Cl
Reactant: CO[C@H]1CN[C@H](c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)C1
Agent: CNC
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)N(C(=O)C(=O)N(C)C)C1
Temperature: 0 °C

Procedure:
To N-(4-fluorobenzyl)-5-hydroxy-2-[(2S,4R)4-methoxypyrrolidin-2-yl]-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide, triethylamine (1 eq.) was added. The reaction mixture was cooled down to 0° C. and methyl chlorooxoacetate (3 eq.) was added. After 1 hour the reaction mixture was concentrated and a big excess of dimethylamine 2M in THF (30 eq.) was added The reaction mixture was concentrated and the desired compound was isolated by HPLC purification (Waters, Symmetry C18, 5 um, 19×50 mm eluting with water and acetonitrile containing 0.1% trifluoroacetic acid) as a 2:8 mixture of rotamers by NMR:
Reaction SMILES: [Br-].Br[CH2:3][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH:32]=O.O>C1COCC1>[Cl:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[C:32]#[CH:3]
Reactant: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1c(F)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of (bromomethyl)triphenylphosphonium bromide (3.3 g, 7.6 mmol) in THF at 0° C. was added potassium tert-butoxide (2.12 g, 18.9 mmol). The reaction was stirred for 30 minutes and a solution of 2-chloro-6-fluorobenzaldehyde (1 g, 6.31 mmol) in THF was added. The reaction was allowed to warm to room temperature overnight and water was added. The solution was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to give 1-chloro-2-ethynyl-3-fluorobenzene (41).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([NH2:6])=[N:2]1.O=[C:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[N:1]1[N:2]=[C:3]([NH:6][CH:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[NH:4][CH:5]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Nc1nc[nH]n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CCC(Nc2nnc[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
To a solution (200 mL) of 1H-1,2,4-triazol-3-amine (11 g) and ethyl 4-oxocyclohexanecarboxylate (28 g) in acetic acid was added sodium cyanoborohydride (35 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (13 g, 40%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.CC1C=CC(S(O[CH2:55][CH2:56][N:57]2[CH2:61][CH2:60][O:59][C:58]2=[O:62])(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:62]=[C:58]1[N:57]([CH2:56][CH2:55][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[CH2:61][CH2:60][O:59]1
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1OCCN1CCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(2-oxooxazolidin-3-yl)ethyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (46%) as a colorless solid: mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.08 (dd, J=7.3, 7.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.78 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.33-4.22 (m, 1H), 4.21-4.00 (m, 2H), 3.93-3.58 (m, 4H), 3.57-3.43 (m, 1H), 3.05-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ178.8, 161.8, 161.3, 158.7, 141.7, 132.4, 129.0, 124.1, 123.7, 120.0, 119.0, 108.3, 93.2, 80.5, 72.5, 62.1, 57.7, 44.3, 41.7, 37.3, 29.0; MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4]/[C:3]/1=[N:11]/[N:12]=[CH:13][C:14]1[N:15]([CH3:19])[CH:16]=[CH:17][N:18]=1.[Br:20][CH:21]([OH:23])[CH3:22]>C(#N)C>[Br-:20].[OH:23][CH2:21][CH2:22][N+:18]1[CH:17]=[CH:16][N:15]([CH3:19])[C:14]=1/[CH:13]=[N:12]\[N:11]=[C:3]1\[S:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]\1[CH3:1]
Reactant: CC(O)Br
Reactant: Cn1ccnc1C=N/N=c1/sc2ccccc2n1C
Solvent: CC#N
Product: Cn1cc[n+](CCO)c1/C=N\N=c1\sc2ccccc2n1C
Product: [Br-]

Procedure:
1.00 g (3.68 mmol) of 1-methyl-1H-imidazol-2-carboxaldehyde [(2E)-3-methyl-1,3-benzothiazol-2(3H)-ylidene] hydrazone from Step 1 and 0.69 g (5.52 mmol) of bromoethanol in acetonitrile were heated at reflux for 2 hours. After the solvent was removed, the precipitate formed was suction-filtered off, washed with ethyl acetate and dried under vacuum.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]3[CH2:15][CH2:14][CH2:13][C:12]3([C:17]([C:19]3([CH3:44])[CH2:23][CH2:22][CH2:21][CH:20]3[C:24]3[CH:43]=[CH:42][C:27]4[N:28]([CH3:41])[C:29]([CH2:31][NH:32][C:33]5[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=5)=[N:30][C:26]=4[CH:25]=3)=[O:18])[CH3:16])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:45][NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][CH:48]=1.[ClH:55].C(=O)([O-])[O-].[NH4+:60].[NH4+:61]>C(O)C>[ClH:55].[CH3:41][N:28]1[C:27]2[CH:42]=[CH:43][C:24]([CH:20]3[CH2:21][CH2:22][CH2:23][C:19]3([C:17]([C:12]3([CH3:16])[CH2:13][CH2:14][CH2:15][CH:11]3[C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([CH2:45][NH:46][C:47]5[CH:52]=[CH:51][C:50]([C:53](=[NH:60])[NH2:54])=[CH:49][CH:48]=5)=[N:4][C:5]=4[CH:10]=3)=[O:18])[CH3:44])=[CH:25][C:26]=2[N:30]=[C:29]1[CH2:31][NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:61])[NH2:40])=[CH:37][CH:38]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C3CCCC3(C)C(=O)C3(C)CCCC3c3ccc4c(c3)nc(CNc3ccc(C#N)cc3)n4C)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C3CCCC3(C)C(=O)C3(C)CCCC3c3ccc4c(c3)nc(CNc3ccc(C(=N)N)cc3)n4C)ccc21
Yield: 63.5 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-(1-methylcyclopent-1-yl) ketone, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 63.5% of theory, C23H27N5O (389.5); EKA mass spectrum: (M+H)+=390.
Reaction SMILES: F[C:2]([F:7])(F)[C:3](O)=O.Cl[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:22]=[C:23]([NH:31][C@H:32]([CH:35](C)[CH3:36])[CH2:33]N)[C:24]4[S:29](=[O:30])[CH2:28][CH2:27][C:25]=4[N:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[CH3:38][S:39](C1C=CC(N2CCNCC2)=CC=1)(=[O:41])=[O:40]>>[F:7][C:2]1[CH:33]=[C:32]([NH:31][C:23]2[C:24]3[S:29](=[O:30])[CH2:28][CH2:27][C:25]=3[N:26]=[C:21]([N:18]3[CH2:19][CH2:20][N:15]([C:12]4[CH:13]=[CH:14][C:9]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:10][CH:11]=4)[CH2:16][CH2:17]3)[N:22]=2)[CH:35]=[CH:36][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)[C@H](CN)Nc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1S(=O)CC2
Reactant: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(N2CCN(c3nc4c(c(Nc5cccc(F)c5)n3)S(=O)CC4)CC2)cc1

Procedure:
Starting from 2-chloro-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl)-(3-fluoro-phenyl)-amine enantiomer 1 and 1-(4-(methyl-sulphonyl)phenyl)piperazine, Example 202 may be prepared as described in Example 28 (see scheme 2, step C, 2.1.3). Analytical HPLC-MS (method D): RT=1.24 min.