Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[CH:24]1([CH2:30][OH:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][O:31][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OCC1CCCCC1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2cnc(OCC3CCCCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with cyclohexylmethanol according to the procedure described in Example 59 to afford 2-(cyclohexylmethoxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=447 (M++1); Rt=5.17 min; 1H-NMR 400 MHz (CDCl3): δ 1.02-1.20 (m, 2H), 1.20-1.40 (m, 4H), 1.64-1.80 (m, 3H), 1.81-1.98 (m, 2H), 4.23 (d, J=9 Hz, 2H), 7.01 (d, J=9 Hz, 2H), 7.22-7.30 (m, 4H), 7.38 (d, J=2 Hz,1H), 8.58 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]I)=[CH:8][O:9][C:5]=2[CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([Cl:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CCI)coc2c1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Product: COc1ccc2c(CCN3CCN(c4cc(Cl)cc5cccnc45)CC3)coc2c1

Procedure:
8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 9, step 6, starting from 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil Yield: 140 mg (33%); (M+H): 422; 1HNMR (400 MHz, CDCl3):δ 8.86˜8.68 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.02˜7.99 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.45˜6.63 (m, 7H); 3.9 (s, 3H); 3.65˜2.71 (m, 12H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)(=[O:19])=[O:18].C1COCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.[Pd+2]>[F:15][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1ccc(-c2ccc(Cl)cc2F)cn1
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nc2)c(F)c1
Temperature: 60 °C
Yield: 29.3 %

Procedure:
5-(4-Chloro-2-fluorophenyl)pyridin-2-amine (100 mg, 0.449 mmol), 2-(methylsulfonyl)phenylboronic acid (112 mg, 0.561 mmol), and chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (33 mg, 0.045 mmol) were placed in a sealable reaction tube under nitrogen. THF (2 mL, sparged with nitrogen) and K3PO4 (2 mL, 0.5 M sparged with nitrogen) were added, and the reaction vessel was sealed and heated at 60° Celsius for 16 hours with vigorous stirring. The mixture was cooled to rt, diluted with EtOAc, and washed with 2 M K2CO3, then dried and concentrated to dryness. The residue was subjected to FCC to provide the title compound (45 mg, 29%). MS (CI): mass calcd. for C18H15FN2O2S, 342.08; m/z found, 343.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.38-8.31 (s, 1H), 8.29-8.22 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.65 (m, 1H), 7.64-7.57 (m, 1H), 7.52-7.45 (m, 1H), 7.42-7.37 (m, 1H), 7.36-7.27 (m, 2H), 6.64-6.59 (m, 1H), 4.66-4.51 (s, 2H), 2.81-2.69 (s, 2H).
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([F:21])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[C:19]([F:20])=[CH:18][N:17]=1
Reactant: C[C@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](O)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a round bottom flask containing (R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (590 mg, 1.96 mmol) was added DCM (4 mL) and TFA (4 mL). Resulting reaction mixture stirred for 1 hr at room temperature. The volatiles were then removed. Residue neutralized with a saturated solution of NaHCO3 and aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a colorless residue of (R)-3-(2,5-difluoropyrimidin-4-yl)-4-((S)-1-hydroxyethyl)oxazolidin-2-one (470 mg, 1.917 mmol, 98% yield). LCMS m/z 246.0 (M+H)+, Rt 0.41 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH3:14])[N:6]=2.CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:1][C:2]1[C:3]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][CH3:14])[N:6]=2)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1nc2nc(OCC)ccc2cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nc2nc(OCC)ccc2cc1NC(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-amino-7-ethoxy-1,8-naphthyridine-2-carboxylate (51 mg, 0.20 mmol) and DIPEA (100 μL, 0.58 mmol) in DCM (0.7 mL), benzyl chloroformate (84 μL, 0.58 mmol) was added and the reaction mixture was heated at 65° C. with stirring in a sealed vial for 16 h. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-40% EtOAc/hexanes) to afford the sub-title compound. LCMS (ESI) calc. for C21H22N3O5 [M+H]+: m/z=396.2. found: 396.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[O:13][CH:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[N:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:22])[O:13][CH:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH:26]=[N:25][CH:24]=1
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(Br)cc1
Reactant: OB(O)c1cncnc1
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(-c2cncnc2)cc1
Yield: 40.4 %

Procedure:
Using general procedure E, quinuclidin-3-yl 2-(4-bromophenyl)propan-2-ylcarbamate (200 mg, 0.540 mmol), pyrimidin-5-ylboronic acid (136 mg, 1.12 mmol) and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (80 mg, 40%). 1H NMR (500 MHz, CDCl3) δ 9.17 (s, 1H), 8.92 (s, 2H), 7.58-7.51 (m, 4H), 5.34 (s, 1H), 4.61 (m, 1H), 3.20-3.10 (m, 1H), 2.92-2.41 (m, 5H), 2.00-1.76 (m, 2H), 1.72-1.53 (m, 7H), 1.52-1.32 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3) δ 157.4, 154.8, 154.5, 148.2, 134.0, 132.5, 127.0, 126.0, 71.2, 55.6, 55.0, 47.4, 46.3, 29.7, 29.4, 25.4, 24.5, 19.5 ppm. Purity: >96% LCMS (214 nm & 254 nm); retention time 1.34 min; (M+1) 366.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:30]1([CH2:33][CH2:34][C:35]([OH:37])=O)[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][CH2:34][C:35]([N:14]([CH:13]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])=[O:37])[CH2:31][CH2:32]1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCC1CC1
Product: CN(C(=O)CCC1CC1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-propionamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-cyclopropylpropionic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 534.3 [M]+.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>CO>[CH:1]1([NH:7][C:8]2[C:13]([CH:14]([OH:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[CH:18]=[CH:19][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1NC1CCCCC1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
1-(4-(Cyclohexylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (13 mg, 0.034 mmol) in methanol (1 mL) was stirred with sodium borohydride (30 mg, 0.79 mmol) at room temperature for 1 hour and at 60° C. for another 5 hours. The reaction mixture was allowed to cool to room temperature and, after addition of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→3/1 (v/v)) to give the title compound as a colorless oil (9.1 mg, yield 70%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][C:4]=1[F:15])[CH3:2].[OH2:16]>O1CCCC1.S(=O)(=O)(O)O.Cl[Hg]Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:16])[CH3:10])=[CH:5][C:4]=1[F:15])[CH3:2]
Reactant: CCc1ccc(C#C[Si](C)(C)C)cc1F
Reactant: O
Agent: Cl[Hg]Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CCc1ccc(C(C)=O)cc1F
Reaction time: 6 h

Procedure:
To a stirred mixture of (4-ethyl-3-fluoro-phenylethynyl)-trimethyl-silane (1.43 g, 6.5 mmol), HgCl2 (250 mg, 0.92 mmol) in aqueous tetrahydrofuran (tetrahydrofuran, 10 mL, H2O, 3 mL), concentrated sulfuric acid (98%, 0.70 mL) was added and the mixture stirred for 6 hours. The mixture was poured into water (50 mL) and extracted with ether (3×20 mL). Removal of solvent gave a solid that was chromatographed (20% thyl acetate/hexanes) to give the desired product. 560 mg, 52%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[OH:15].FC1C=CC([N+]([O-])=O)=CC=1O.CN1CCNCC1.[CH2:34]1[C:42]2[C:37](=[CH:38][C:39]([N:43]3[C:48]4[N:49]=[C:50](S(C)(=O)=O)[N:51]=[CH:52][C:47]=4[C:46](=[O:57])[C:45]([C:58]([NH2:60])=[O:59])=[CH:44]3)=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>>[OH:15][C:3]1[CH:4]=[C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:50]1[N:51]=[CH:52][C:47]2[C:46](=[O:57])[C:45]([C:58]([NH2:60])=[O:59])=[CH:44][N:43]([C:39]3[CH:38]=[C:37]4[C:42](=[CH:41][CH:40]=3)[CH2:34][CH2:35][CH2:36]4)[C:48]=2[N:49]=1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C(N)=O)cn(-c3ccc4c(c3)CCC4)c2n1
Reactant: CN1CCN(c2ccc(N)c(O)c2)CC1
Agent: CN1CCNCC1
Agent: O=[N+]([O-])c1ccc(F)c(O)c1
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C(N)=O)cn(-c5ccc6c(c5)CCC6)c4n3)c(O)c2)CC1
Yield: 40 %

Procedure:
Using the procedure outlined in Example 23 (c), the title compound was prepared from 2-amino-5-(4-methyl-piperazin-1-yl)-phenol (5 mg, prepared using the procedure outlined in Example 1 (F) from 1-fluoro-2-hydroxy-4-nitrobenzene and 1-methyl-piperazine) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg). Purification by preparative HPLC (32 mL/min, 5-100% H2O/MeCN (0.01% TFA, v/v) gradient over 10 min) followed by a basic aqueous work-up gave the title compound as a yellow solid (3.7 mg, 40%). 1H NMR (400 MHz, CD3OD) δ (ppm): 9.25 (br, 1H), 8.73 (s, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.25 (d, J=7.1 Hz, 1H), 6.45 (s, 1H), 6.02 (br, 1H), 3.20 (br, 2H), 3.03 (m, 6H), 2.65 (s, 3H), 2.22 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H29N7O3: 512.23 (M+H), Found: 512.1.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[Na].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[CH:21][CH:20]=1.[OH-].[Na+]>C(O)C.O>[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:4]2[C:5](=[O:14])[C:6]3[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:15])=[CH:21][CH:20]=1
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: COc1ccc(OCCCCBr)cc1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCn1cnc2c1c(=O)n(CCCCOc1ccc(OC)cc1)c(=O)n2C
Yield: 64.8 %

Procedure:
3-Methyl-7-propylxanthine (10.4 g) was dissolved in 200 ml of an ethanol/water (3:2 (v/v)) mixed solution containing 2.2 g of sodium hyddroxide and 15.5 g of 4-(4-methoxyphenoxy)butylbromide was added to the solution. The mixture was then refluxed at elevated temperatures for 12 hours. The reaction mixture was concentrated under reduced pressure to give the residual liquid which in turn was alkalized with 1N-sodium hydroxide solution and then extracted with chloroform. The extract was dried and concentrated under reduced pressure to dryness. The residue was then subjected to silica gel column chromatography using a chloroform/ethanol (40:1 (v/v)) eluent to yield 12.5 g (65%) of 1-[4-(4-methoxyphenoxy)butyl]-3-methyl-7-propylxanthine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:21])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2cc(F)cc(Cl)c2)CCNC1
Reaction time: 4 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3-Chloro-5-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (1.6 g, 5.08 mmol), dichloromethane (3 mL) and trifluoroacetic acid (3 mL). Stirred for 4 h. Purification on a Biotage (solute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) and by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 20:80 to 100:0). Yield: 1.1 g. MS m/z (rel. intensity, 70 eV) 215 (M+, bp), 129 (65), 109 (52), 157 (46), 95 (44).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11]Br)=[CH:8][C:9]=1[Cl:10])=[O:4].C([O-])(O)=[O:14].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:14])=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: O=C([O-])O
Reactant: COC(=O)c1sc(CBr)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1sc(CO)cc1Cl
Temperature: 115 °C
Yield: 44.6 %

Procedure:
A mixture of 5-Bromomethyl-3-chloro-thiophene-2-carboxylic acid methyl ester (3.8 g, 14.1 mmol) and NaHCO3 (20 g, 238 mmol) in DMSO (100 ml) was heated at 115° C. for 4 h. The reaction mixture was cooled. The reaction mixture was diluted with water and extracted with DCM (3×100 mL), washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column (0-30% EtOAc in hexane) to give 1.30 g (45%) product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:10]=3[NH:11][C:12](=[N:18][NH2:19])[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:10]=3[N:11]3[C:30](=[O:31])[NH:19][N:18]=[C:12]3[C@@:13]3([CH2:16][C@H:15]3[CH3:17])[N:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)C(=NN)N2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C)c1n[nH]c(=O)n1-2
Temperature: 85 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
A disposable tube was charged with (1S,2R)-5′-(4-chlorophenyl)-2′-hydrazono-2,6′,7′-trimethyl-1′,2′-dihydrospiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepine] (24 mg, 0.067 mmol) and a stir bar. THF (1.5 mL, 0.05 M) was added, followed by CDI (13.01 mg, 0.080 mmol), and the solution was stirred 85° C. 4 h. At 4 h, more CDI (26 mg, 0.160 mmol) was added, and the reaction was stirred at 85° C. The reaction was concentrated and purified by reverse phase chromatography (water/acetonitrile with 0.1% TFA) to give (1S,2R)-4′-(4-chlorophenyl)-2,2′,3′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin]-9′(8′H)-one (2,2,2-trifluoroacetic acid salt) (Compound 222) as a yellow amorphous solid (17 mg). LRMS (M+H)+: 385 m/z. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 7.49 (d, J=8.90 Hz, 2H), 7.42 (d, J=8.70 Hz, 2H), 2.34 (s, 3H), 1.52 (s, 3H), 1.18 (s, OH), 1.16 (s, 1H), 1.15 (s, 1H), 0.87 (br. s., 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(OC(C)C)(C)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CS(=N)(=O)c1ccc(N)cc1

Procedure:
A solution of 2.45 g (12.2 mmol) of (RS)-S-(4-nitrophenyl)-S-methyl sulfoximide in 150 ml of ethanol is hydrogenated at room temperature with use of 0.80 g of Pd/C (10%×50% H2O) under a hydrogen atmosphere at normal pressure over 4 hours. The hydrogen absorption is 920 ml. The batch is filtered and concentrated by evaporation. The residue that is obtained is digested with diisopropyl ether. 1.90 g (11.2 mmol, corresponding to 92% of theory) is obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:22][CH:21]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([C:26]([CH3:30])([CH3:29])[C:27]#[N:28])=[CH:24][CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C#N)c1ccc(N)cc1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Solvent: CC#N
Product: CC(C)(C#N)c1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Yield: 88.2 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (40 mg, 0.14 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (100 mg, 0.63 mmol) (prepared according to the reference: Axton, C. A. et al, J. Chem. Soc. Perkin Trans. 1, 1992, 2203.), and acetonitrile (0.5 mL) was heated with microwave at 180° C. for 60 min. The solvent was removed in vacuo and the residue was purified by chromatography to give a light yellow solid (50 mg, 58%).
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=3[CH:35]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[NH:1]1[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:9][N:3]=[N:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Temperature: 105 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Azidotrimethylsilane (161 μL, 1.215 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (225 mg, 0.607 mmol) and dibutylstannanone (30 mg, 0.121 mmol) in toluene (6 mL) at rt. It was heated to 105° C. and allowed to stir overnight. The reaction, which remained a slurry, resulted in ˜70% conversion. Additional equiv of reagents and solvents were added and the mixture was allowed to stir overnight at 105° C. The reaction was allowed to cool and filtered to give the titled compound (205 mg, 82%). LC-MS retention time: 1.03 min; m/z (MH+): 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[N:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:5][C:4]=1O)[CH3:2].P(Cl)(Cl)(Cl)=O.[NH3:32]>C(#N)C>[CH2:1]([C:3]1[N:8]=[N:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:5][C:4]=1[NH2:32])[CH3:2]
Reactant: N
Reactant: CCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.800 g (5.138 mmol) of 6-ethyl-3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazin-5-ol were admixed with 25 ml of phosphoryl chloride and stirred overnight at RT. The reaction mixture was diluted with 100 ml of dry acetonitrile and, with ice-cooling, stirred into 375 ml of concentrated aqueous ammonia solution (25% strength). Stirring was carried out for 4 h at RT. Concentration on a rotary evaporator was carried out and the residue was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulphate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water with 0.1% TFA, gradient 30:70→95:5). This gave 157 mg (8% of theory) of the target compound.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[C:29]2C(=[CH:25][CH:26]=[CH:27][CH:28]=2)C=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:27]([CH2:26][CH3:25])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M−15, 0.1), 237 (15), 236 (100), 163 (5), 121 (19), 114 (7).