Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([N+:17]([O-])=O)=[CH:11][CH:12]=3)[C:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[CH:5]=1)([O-])=O.[H][H].C.CC(=O)OCC>C(O)C.O1CCCC1.[Pd].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([NH2:17])=[CH:11][CH:12]=3)[C:7]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[CH:5]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc([N+](=O)[O-])ccc2-c2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCC1(CCCCCCCC)c2cc(N)ccc2-c2ccc(N)cc21

Procedure:
2,7-Dinitro-9,9-dioctylfluorene (27.84 g, 57.93 mmol) was dissolved in absolute ethanol (90 mL) and tetrahydrofuran (THF, 50 mL). Palladium on carbon (5%, 0.5 g) was subsequently added. The mixture was placed on a Parr hydrogenator and shaken under 40 psi of hydrogen for 4 hrs. at room temperature. The mixture was filtered through CELITE® and the solvent removed by rotary evaporation to afford a red-brown liquid. The crude product was dissolved in CHCl3 and stirred with decolorizing charcoal for 1 hr. at room temperature. The solution was filtered and the solvent removed by rotary evaporation to give a red liquid that slowly solidified into needle-like crystals (mp 58-63° C.). Yield=22.36 g (91.76%). 1H NMR (300 MHz, CDCl3) δ 0.7 (m, 4H), 0.8 (t, 6H), 1.0-1.3 (m, 20H), 1.9 (m, 4H), 3.6 (s, 4H), 6.6 (m, 4H), 7.3 (d, 2H) ppm. 13C NMR (75 MHz, CDCl3) δ 15, 23, 24, 30, 30, 31, 32, 41, 55, 111, 114, 119, 134, 145, 152 ppm. EA calcd. for C29H46N2: % C, 82.80; % H, 10.54; % N, 6.66. Found: % C, 82.29; % H, 10.06; % N, 6.73.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[N:3]=1.B1(C=C)OB([CH:17]=[CH2:18])OB(C=C)O1.C1C=CN=CC=1>COCCOC.C([O-])([O-])=O.[K+].[K+].O.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>[Br:10][C:4]1[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=[C:2]([CH:17]=[CH2:18])[N:3]=1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: COc1cc(Br)nc(Br)c1
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: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: C=Cc1cc(OC)cc(Br)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 159.3 %

Procedure:
To a suspension of 2,6-dibromo-4-methoxy-pyridine (5.90 g, 22.1 mmol) in DME (60 mL) and 2 M aq. K2CO3-solution (20 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (3.19 g, 13.2 mmol) is added and the mixture is degassed and put under N2 before Pd(PPh3)4 (460 mg, 0.398 mmol) is added. The mixture is stirred at 85° C. for 2 h before it is again cooled to rt, diluted with water and extracted with EA. The org. extract is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-bromo-4-methoxy-6-vinyl-pyridine (4.50 g) as a yellow solid; LC-MS: tR=0.90 min, [M+1]+=213.83.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2=[CH:14][N:15]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:16]=[C:12]2[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(OCC)C>C(Cl)Cl>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[N:15]1[CH:14]=[C:13]2[C:8]([NH2:7])=[N:9][CH:10]=[CH:11][C:12]2=[N:16]1
Reactant: CC(C)(C)OC(=O)Nc1nccc2nn(-c3c(F)cccc3Cl)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1nccc2nn(-c3c(F)cccc3Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a solution of [2-(2-chloro-6-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-carbamic acid tert-butyl ester (137 mg) in DCM (1 mL)) at 0° C. was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 hour then concentrated under reduced pressure. The resultant residue was partitioned between ethyl acetate and sodium bicarbonate (sat. aq.). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give a colourless oil. Trituration with diethyl ether gave the title compound as a white solid (100 mg, 91% yield). LCMS (Method C): RT=0.34 min and 1.79 min, m/z: 263 [M+H+].
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:9]1[C:13]([C@@H:14]([OH:37])[C@@H:15]([C:25](N2[C@H](C(C)C)CCOC2=O)=[O:26])[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][N:11]=[CH:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[NH4+]>CO>[CH2:3]([N:9]1[C:13]([C@@H:14]([OH:37])[C@H:15]([CH2:25][OH:26])[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][N:11]=[CH:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCn1cncc1[C@@H](O)[C@H](C/C=C\CCC(=O)OC)C(=O)N1C(=O)OCC[C@H]1C(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCCCCCn1cncc1[C@@H](O)[C@H](CO)C/C=C\CCC(=O)OC
Yield: 60 %

Procedure:
Sodium borohydride (4×36 mg, 3.8 mmol) was added in batches at 30 minute intervals to a solution of the product of step (v) in methanol (4 ml) at 0° C. with stirring under argon. After stirring for a further 30 minutes, a saturated aqueous solution of ammonium chloride (5 ml) was added slowly. The mixture was extracted with ethyl acetate (3×10 ml) and the combined extracts dried (MgSO4), filtered and concentrated by evaporation. The residue was purified by column chromatography, eluting with 10% methanol/dichloromethane (v/v), to give methyl (7S,4Z)-7-[(S)-(1-hexylimidazol-5-yl)hydroxymethyl]-8-hydroxyoct-4-enoate (200 mg, 60% yield) as an oil;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.NCC1C=CC(C(OC)=O)=CC=1[F:42]>>[F:42][C:29]1[CH:28]=[C:23]([CH:22]=[CH:21][C:20]=1[CH2:19][NH:18][C:16]([C:4]1[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:17])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(CN)c(F)c1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Product: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(aminomethyl)-3-fluorobenzoate: 1H-NMR (CDCl3) δ 8.45–8.33 (2H, m), 8.04 (1H, d, J=3.1 Hz), 7.80 (1H, dd, J=7.9, 1.5 Hz), 7.71 (1H, dd, J=10.5, 1.5 Hz), 7.49 (1H, t, J=7.6 Hz), 7.17–7.12 (4H, m), 4.78 (2H, d, J=6.1 Hz), 3.91 (3H, s); MS (ESI) m/z 417 (M+H)+, 415 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].CCN(C(C)C)C(C)C.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30]>C(OCC)(=O)C.CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(N)CN1C(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(NC(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-Amino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2.45 g, 10 mmol) in ethyl acetate (20 mL) and methanol (5 mL) was added DIPEA (0.15 g, 1.14 mmol) followed by ethyl trifluoroacetate (1.54 g, 11 mmol). The reaction mixture was stirred at room temperature overnight and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid which was used directly to the next step without further purification.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[C:11]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:12][C@H:13]2[C:18](=[O:20])[NH2:19])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[C:18]([C@@H:13]1[CH:12]=[C:11]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[OH:8])(=[O:20])[NH2:19]
Reactant: CC(C)(C)OC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OCc1ccccc1)C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(O)C2=O
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl 2-((2S,5R)-6-(benzyloxy)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-4-yl)ethylcarbamate (Intermediate 227, 0.300 g, 0.72 mmol) in EtOAc (5 mL) was added 10% Pd/C (0.077 g, 0.72 mmol). The reaction mixture was stirred under hydrogen for 30 minutes. The reaction mixture was filtered through celite and washed with EtOAc. The solvent was removed in vacuo to give the title compound as a white solid (0.23 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([O:14]COCC)([CH2:12][F:13])[CH2:10][F:11].[Li]CCCC.[B:24](OC)(OC)[O:25]C.CC(=O)OCC>C1COCC1>[F:11][CH2:10][C:9]1([CH2:12][F:13])[O:14][B:24]([OH:25])[C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]1=2
Reactant: CCOCOC(CF)(CF)c1cc(C)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2c(c1)C(CF)(CF)OB2O
Reaction time: 0.17 h
Yield: 32.4 %

Procedure:
To a solution of 1-bromo-2-(2-(ethoxymethoxy)-1,3-difluoropropan-2-yl)-4-methylbenzene (1.8 g, 5.10 mmol) in THF (15 mL) at −78° C. was slowly added n-BuLi (5.1 mL, 12.75 mmol). After stirring for 10 min, a solution of B(OMe)3 (1.06 g, 10.2 mmol) in dry THF (5 mL) was added dropwise. The mixture was stirred at −78° C. for 0.5 h, and then dry ice bath was removed. The solution was acidified with HCl (4 N) and extracted with EA (100 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (5:1 to 3:1) to give the desired compound (350 mg, yield 32%) as white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1.[CH2:23]([O:26][C:27]([N-:29][S:30]([NH2:33])(=[O:32])=[O:31])=[O:28])[CH:24]=[CH2:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[CH2:23]([O:26][C:27]([N:29]([CH2:14][C:15]1[N:16]2[CH:22]=[N:21][CH:20]=[C:17]2[S:18][CH:19]=1)[S:30]([NH2:33])(=[O:32])=[O:31])=[O:28])[CH:24]=[CH2:25]
Reactant: OCc1csc2cncn12
Reactant: C=CCOC(=O)[N-]S(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCOC(=O)N(Cc1csc2cncn12)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.3 %

Procedure:
Under an argon atmosphere at -51° C., 0.71 ml of diethyl azodicarboxylate was added dropwise to 5 ml of an anhydrous tetrahydrofuran solution containing 463 mg of 3-hydroxymethylimidazo[5,1-b]thiazole, 811 mg of N-allyloxycarbonyl-N-aminosulfonylamide and 1180 mg of triphenylphosphine, and the mixture was then stirred at -51° C. to -37° C. for 15 minutes and further stirred for 70 minutes, while the solution was heated up to room temperature. The solvent was evaporated under reduced pressure to obtain an oil, and this oil was then dissolved in 50 ml of ethyl acetate. Further, the solution was extracted with 2N hydrochloric acid (30 ml×2), and the combined aqueous layer was then washed with 20 ml of ethyl acetate. After neutralized (pH 7) with sodium hydrogencarbonate, the neutralized solution was extracted with ethyl acetate (100 ml×2). The thus extracted organic layer was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. Afterward, the resulting oil was purified by a silica gel column chromatograph and successively Cephadex LH-20 to obtain 145.6 mg of the title compound in a milky white amorphous state.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]3[C:23]=2[CH3:24])=[CH:7][C:6]=1[N+:25]([O-:27])=[O:26])(=O)C.Cl>C(O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][N:16]3[C:23]=2[CH3:24])=[CH:7][C:6]=1[N+:25]([O-:27])=[O:26]
Reactant: COc1ccn2c(C)c(C=Cc3ccc(NC(C)=O)c([N+](=O)[O-])c3)nc2c1
Agent: Cl
Solvent: CCO
Product: COc1ccn2c(C)c(C=Cc3ccc(N)c([N+](=O)[O-])c3)nc2c1
Temperature: 25 °C
Yield: 105 %

Procedure:
A mixture of 2-[2-(4-acetamido-3-nitrophenyl)vinyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (8.2 g) in ethanol (80 ml) and 6N-hydrochloric acid (80 ml) was refluxed for 4 hours and the mixture was cooled to ambient temperature. The isolated precipitate was collected by filtration. To a precipitate was added water, and a mixture was adjusted to pH 8 with saturated aqueous potassium carbonate. The precipitate was collected by filtration and dried to give 2-[2-(4-amino-3-nitrophenyl)vinyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (7.62 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].[N+:42]([C:45]1[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=1)([O-:44])=[O:43]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:8](/[CH:10]=[CH:49]/[C:48]2[CH:51]=[CH:52][C:45]([N+:42]([O-:44])=[O:43])=[CH:46][CH:47]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(NC(C)=O)nc1/C=C/c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirring solution of ethyl 2-(acetylamino)-4-(chloromethyl)-1,3-thiazole-5-carboxylate (1.0 g, 3.81 mmol) in N,N-dimethylformamide (20 mL) was added triphenylphosphine (1.2 g, 4.57 mmol) at room temperature. The resultant mixture was stirred at 65° C. for 5 hours. To the mixture was added potassium tert-butoxide (555 mg, 4.95 mmol) at 5° C., and the resultant mixture was stirred at 5° C. for 30 minutes. p-Nitrobenzaldehyde (805 mg, 5.33 mmol) was added at 5° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][CH:51]=[C:52]([CH3:54])[N:53]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][CH:51]=[C:52]([CH3:54])[N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Cc1csc(N)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.4 %

Procedure:
A solution of triphenylphosphine (345 mg, 1.31 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (234 mg, 1.31 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (300 mg, 1.01 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-amino-4-methylthiazole (288 mg, 2.52 mmol). The resulting reaction mixture was allowed to stir at 25° C. for 20 h. The reaction mixture was then diluted with water (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(4-methyl-thiazol-2-yl)-propionamide (192 mg, 48%) as an off-white foam: mp 83–87° C. (foam to gel); [α]23589=−35.7° (c=1.01, chloroform); EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1227.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23]O)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.S(Cl)(Cl)=O.[Cl-].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N:18]4[C:22]([CH2:23][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[CH:21][N:20]=[N:19]4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3nncc3CN3CCCC3)c1)=N2

Procedure:
The title compound was prepared from 8-chloro-4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isobutyl-methyl-amino)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example101) (226 mg, 0.50 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with pyrrolidine in DMF according to the method described in Example 45. Obtained as a light yellow solid (163 mg, 64%).
Reaction SMILES: C([Li])(CC)C.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN(C)CCN(C)C.CN([CH:40]=[O:41])C>C1COCC1>[CH2:6]([O:13][C:14]1[C:15]([CH:40]=[O:41])=[C:16]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[C:17]([N:19]([CH2:20][CH3:21])[CH2:22][CH3:23])=[O:18])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1C=O
Temperature: -70 °C
Reaction time: 4 h
Yield: 27.5 %

Procedure:
1.3 M sec-butyl-lithium in cyclohexanelhexane (54 ml, 0.07 moles) was dropped into a solution under nitrogen of 3-benzyloxy-N,N-diethyl-4-methoxy-benzamide (20 g, 0.064 moles), obtained as described in example 31, tetramethylethylendiamine (10.56 ml, 0.07 moles) in THF (2.25 l) under stirring in a dry ice bath at −70° C. After 2 hours at constant temperature, DMF (21.75 ml, 0.28 moles) was added. The temperature was kept constant for 4 hours then left overnight. The mixture was poured into a NaH2PO4/Na2HPO4 buffer solution (1 l) at pH=7, the phases were separated, the organic one was washed with water (1 l), dried and brought to dryness. The crude was chromatographed (eluent: benzene:ethyl acetate 1:1) to give 6 g of the title compound (yield: 27.4%).
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4]1.[Na].C[OH:34]>C1COCC1.O>[CH3:1][S:2]([CH:3]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:5]2([CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4]1)=[O:34]
Reactant: CSC1CC2(CCN(C(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c2ccccc21
Reactant: CO
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)C1CC2(CCN(C(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 35 h

Procedure:
To a solution of 2,3-dihydro-1-methylthio-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide (1100, 55.4 mg, 0.129 mmol) in methanol (3.0 mL), THF (2.0 mL) and H2O (1.0 mL) was added sodium meta periodade (34.6 mg, 0.161 mmol). After being stirred for 35 h at room temperature, the resulting mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue was triturated with ethyl acetate and isopropyl ether to give 2,3-dihydro-1-methylsulfinyl-N-4-biphenylylspiro[1H-indene-3,4′-piperidine]-1′-carboxamide 45.4 mg; 79%) as an amorphous solid, 1200.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:47]=[CH:46][C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][C:22]([O:24][Si](C(C)(C)C)(C)C)=[CH:23][C:18]=3[N:17]=[C:16]2[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)=[CH:34][CH:33]=2)=[CH:12][C:11]=1[O:48][CH3:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:50]>O>[ClH:50].[ClH:50].[CH2:1]([NH:8][CH2:9][C:10]1[CH:47]=[CH:46][C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:18]=3[N:17]=[C:16]2[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:34][CH:33]=2)=[CH:12][C:11]=1[O:48][CH3:49])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Cn2c(-c3ccc(OCCN4CCCC4)cc3)nc3cc(O[Si](C)(C)C(C)(C)C)ccc32)ccc1CNCc1ccccc1
Agent: Cl
Solvent: O
Product: COc1cc(Cn2c(-c3ccc(OCCN4CCCC4)cc3)nc3cc(O)ccc32)ccc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To the benzyl amine (Example 4, Part A; 20 mg, 0.03 mmol) was added 6 N HCl (1 mL) and the mixture stirred at room temperature for 1 h. The solution was diluted with 5 mL of H2O, washed with Et2O, and the aqueous layer concentrated under reduced pressure; yielding 17 mg (89%) of the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)=[C:17]([CH3:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:33][CH2:32]1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCCl)c23)ccc1OCc1ccccn1
Reactant: CN1CCNCC1
Product: Cc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccn1
Yield: 28 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-methyl-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 28% yield; NMR Spectrum: 2.11 (s, 3H), 2.24 (s, 7H), 2.51 (hidden by DMSO, 4H), 2.77 (t, 2H), 4.41 (t, 2H), 5.21 (s, 2H), 6.99 (d, 1H), 7.35 (t, 1H), 7.44 (s+d, 2H), 7.54 (d, 1H), 7.84 (t, 1H), 8.21 (s, 1H), 8.24 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 475 (MH+).