Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:20])[CH:3]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24].C(N(CC)CC)C>C(O)C>[CH:15]1([O:14][C:7]2[C:8]([O:12][CH3:13])=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][C:4](=[O:20])[CH:3]=[C:2]3[NH:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1ccc2c(Cl)cc(=O)oc2c1OC1CCCC1
Reactant: NCC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c(NCC(=O)O)cc(=O)oc2c1OC1CCCC1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
A mixture of 4-chloro-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (170 mg, 0.58 mmol), glycine (52 mg, 0.69 mmol), triethylamine (0.2 mL, 1.4 mmol), and ethanol (2 mL) was heated at 75° C. in a sealed vial. After 2 d, more glycine (136 mg, 1.8 mmol) and triethylamine (0.3 mL, 2.2 mmol) were added. The reaction was heated at 75° C. for an additional day, allowed to cool to rt, concentrated, diluted with ethyl acetate (40 mL), and then washed with 1N HCl (50 mL×3). The organic layer was dried, filtered, and concentrated to give 2-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)acetic acid: 1H NMR (400 MHz, DMSO-d6): δ 7.87 (t, 1H), 7.68 (d, 1H), 7.08 (d, 1H), 4.88 (s, 1H), 4.81 (m, 1H), 4.00 (d, 2H), 3.87 (s, 3H), 1.90-1.44 (m, 8H); MS (ESI): 333.9.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]1([S:39](Cl)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.O>C(Cl)Cl>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([S:39]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)(=[O:41])=[O:40])[CH2:13][CH2:12]3)=[O:28])=[CH:22][CH:21]=2)[CH:27]=[N:26][N:25]=[N:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(-n3cnnn3)cc2)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccc(-n2cnnn2)cc1)N1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
In a two neck round bottom flask, 2-(4-(1H-tetrazol-1-yl)phenoxy)-1-(piperazine-1-yl)ethanone hydrochloride (compound 3, 0.882 mmoles, 0.286 g, 1 eq) and 1-naphthalene sulfonylchloride (0.882 mmoles, 0.2 g, 1 eq) were charged in DCM (20 mL). TEA (2.646 moles, 0.267 g, 3 eq) was added drop wise to the reaction mixture over a period of 10 min at 0° C. The resulting mixture was stirred for 3 h at room temperature and monitored by TLC. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 3:7, Ethyl acetate/Hexane) to obtain the title compound (0.300 g, 71.09%) as off-white solid.
Reaction SMILES: [OH-].[NH4+:2].[Cl-].[NH4+:4].[C-:5]#N.[Na+].[CH3:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O>>[NH2:2][C:12]1([C:5]#[N:4])[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: CN1CCCCC1=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(N)(C#N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Using the procedure of Stage 1 of Example 1, 8 ml of ammonium hydroxide, 1.58 g of ammonium chloride and 1.23 g of sodium cyanide were reacted and 2.5 ml of 1-methylpiperidone were added. The mixture was stirred for 18 hours at ambient temperature, followed by extraction 3 times with chloroform. The organic phase was washed with salt water and dried to obtain 2.41 g of the expected product (orange-yellow syrup).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:18][C:17]=1[F:31])=[O:14].Cl>C(Cl)Cl.[Na].[H][H]>[F:31][C:17]1[CH:18]=[C:19]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH:20]=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[CH2:12][NH:11][CH:1]=[O:3]
Reactant: NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na]
Solvent: O=CO
Solvent: ClCCl
Product: O=CNCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Temperature: 0 °C
Yield: 91 %

Procedure:
A mixture of acetic anhydride (40 mg, 0.39 mmol) and formic acid (22 mg, 0.48 mmol) was stirred at 0° C. and then heated uat 60° C. for 1 h. Step 2: During this time, 2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide (1:1) hydrochloride (50 mg, 0.15 mmol) was extracted with DCM and sodium hydrogen carboante (saturated) and the organic layer evaporated. Then to a mixture of the acetic formic anhydride (Step 1) in dry THF (0.5 mL) was added a solution of the amine (Step 2) in dry THF (1 mL) at room temperature and the resulting mixture stirred for 10 min. Then the reaction mixture was evaporated leave the title compound (44.1 mg, 91%) as a white solid. MS: m/e=321.1 (M++H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[CH2:31][CH2:30][N:29]2[C:24](=NCCC2)[CH2:23][CH2:22]1.C1(C=CC#N)CC1.O>CN(C=O)C>[CH:21]1([CH:22]([N:15]2[CH:14]=[C:13]([C:11]3[N:10]4[CH:18]=[CH:19][N:20]=[C:9]4[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:12]=3)[CH:17]=[N:16]2)[CH2:23][C:24]#[N:29])[CH2:31][CH2:30]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Agent: N#CC=CC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
To a solution of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation; K-1; 0.130 g, 0.490 mmol) in dry DMF (2 mL) was added DBU (89.5 mg, 0.588 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.183 g, 1.96 mmol). The reaction mixture was stirred at ambient temperature for 24 hours. Additional 3-cyclopropylacrylonitrile (0.046 g, 0.49 mmol) was added and the reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was added to H2O (8 mL), mixed and extracted with EtOAc. The combined EtOAc extracts were washed with saturated NaCl and dried over MgSO4/activated carbon. The solution was eluted through a short SiO2 column (15 mL course frit funnel, ½ full of SiO2) eluting first with EtOAc, then with 10% MeOH/EtOAc. The 10% MeOH/EtOAc fraction was concentrated and the resulting residue treated with Et2O and sonicated to give a granular suspension. The precipitate was allowed to settle, Et2O decanted off, solid washed with Et2O and then dried under vacuum to provide a 3-cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (40 mg, 23% yield) as a white powder. MS (apci) m/z=359.2 (M+H).
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CNCCCCCCCCNC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)(C(C)(C)C)(C)C.[NH2:67][CH2:68][C@@H:69]([C:78]1[C:83]2[O:84][CH2:85][C:86](=[O:88])[NH:87][C:82]=2[CH:81]=[C:80]([OH:89])[CH:79]=1)[O:70][Si:71]([C:74]([CH3:77])([CH3:76])[CH3:75])([CH3:73])[CH3:72].[CH3:90][O:91][C:92]1[CH:93]=[C:94]([NH:98][C:99]2[C:108]3[C:103](=[C:104]([CH3:124])[CH:105]=[C:106]([S:109]([CH2:112][CH2:113][CH2:114][CH2:115][CH2:116][CH2:117][CH2:118][CH2:119][CH2:120][CH2:121][CH:122]=O)(=[O:111])=[O:110])[CH:107]=3)[N:102]=[CH:101][C:100]=2[C:125]([NH2:127])=[O:126])[CH:95]=[CH:96][CH:97]=1>>[Si:71]([O:70][C@H:69]([C:78]1[C:83]2[O:84][CH2:85][C:86](=[O:88])[NH:87][C:82]=2[CH:81]=[C:80]([OH:89])[CH:79]=1)[CH2:68][NH:67][CH2:122][CH2:121][CH2:120][CH2:119][CH2:118][CH2:117][CH2:116][CH2:115][CH2:114][CH2:113][CH2:112][S:109]([C:106]1[CH:107]=[C:108]2[C:103](=[C:104]([CH3:124])[CH:105]=1)[N:102]=[CH:101][C:100]([C:125]([NH2:127])=[O:126])=[C:99]2[NH:98][C:94]1[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH3:90])[CH:93]=1)(=[O:111])=[O:110])([C:74]([CH3:77])([CH3:75])[CH3:76])([CH3:73])[CH3:72]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCC=O)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1cc(O)cc2c1OCC(=O)N2
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c4cc(O)cc5c4OCC(=O)N5)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 148, using (R)-8-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-6-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one in place of Intermediate 2 and Intermediate 126 in place of Intermediate 112. ES/MS calcd. for C45H64N5O8SSi+ 862.4. Found m/z=862.6 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:39][CH2:40][CH:41]([N:44]4[CH2:50][CH2:49][C:48](=[O:51])[NH:47][CH2:46][CH2:45]4)[CH2:42][CH2:43]3)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCN(C2CCNCC2)CCN1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCNC(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-piperidin-4-yl-[1,4]diazepan-5-one (ChemBridge) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C38H48N7O3Cl2 [(M+H)+] 720.319, observed 720.3196.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.[CH3:15][NH2:16]>O>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]1[C:2]([NH:16][CH3:15])=[N:3][S:4][N:5]=1
Reactant: CN
Reactant: Clc1cccc(Cl)c1-c1nsnc1Cl
Solvent: O
Product: CNc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 120 °C
Reaction time: 12 h

Procedure:
In a stainless steel vessel, 5.31 g of 3-chloro-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 100 ml of 40% aqueous methylamine solution were placed. After sealing the vessel, the solution was stirred at 120° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed three times with water and three times with saturated aqueous sodium chloride solution. The resultant was then dried over anhydrous sodium sulfate and then the resultant was concentrated, followed by purification by silica gel column chromatography to obtain 2.55 g of 3-(2,6-dichlorophenyl)-4-methylamino-1,2,5-thiadiazole.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH2:14]O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH3:2].CCN(CC)CC.CS([Cl:27])(=O)=O.[Li+].[Cl-]>C(Cl)Cl.CN(C=O)C>[Cl:27][CH2:14][CH2:13][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CCO)c1cccc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CCCl)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A stirred solution of the above alcohol (XI; R=H) (4.0 g, 19 mmol) in CH2Cl2 (35 mL) containing NEt3 (2.91 mL, 21 mmol) was treated dropwise at 0 ° C. with methanesulfonylchloride (1.62 mL, 21 mmol). After being stirred at 0 ° C. for a further 30 min and at20 ° C. for 30 min, the reaction mixture was diluted with CH2Cl2 (35 mL) and washed successively with 1N HCl, 1N Na2CO3and saturated NaCl, and worked up to give the crude mesylate, which was immediately treated with LiCl (2 g) in dry DMF (20 mL) at 75° C. for 30 min. Removal of excess solvent under reduced pressure, and chromatography of the residue on SiO2 (EtOAc/petroleum ether, 1:4 ) gave N-(2-chloroethyl)-N-ethyl-3-nitroaniline (XII; R=H) (3.58 g, 82%)as yellow prisms, mp (petroleum ether) 56°-57 ° C. 1H NMR (CDCl3) 7.51 (dd, J=7.9, 1.9 Hz, 1 H, H-4), 7.48 (t, j=2.4 Hz, 1 H, H-2), 7.32 (m, 2 H, H-5), 6.95 (dd, J=8.4, 2.7 Hz, H-6), 3.70 (m, 2 H, NCH2CH2Cl), 3.64 (m, 2 H, CH2Cl), 3.50 (q, J=7.1 Hz, 2 H, NCH2CH3), 1.22 (t, J=7.1 Hz, 3 H, CH3). Anal.(C10H13ClN2O2) C,H,N,Cl.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][Cl:28])=[CH:25][CH:24]=1)([O-:22])=[O:21]>CC#N.CCOCC>[Cl-:28].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Cl-]
Temperature: 25 °C
Yield: 84.1 %

Procedure:
Triphenylphosphine (38.17 g, 0.146 mole) and 4-nitrobenzyl chloride (25g, 0.146 mole) were dissolved in CH3CN (100 mL) and heated at reflux for 2 hours, and then allowed to cool to room temperature. The reaction mixture was diluted with Et2O (300 mL), the white solid was filtered, washed with Et2O (200 mL), and dried in vacuo, giving 53.3 g (84%) of 4-nitrobenzyltriphenylphosphonium chloride as a single spot on TLC: (Rf =0.71, 4:1:1 butanol:acetic acid:water). 1H-NMR (d6 -DMSO): 5.40-5.50 (2H, d, CH2P, J=20 Hz); 7.20-7.40 (2H, dd, aromatic); 7.40-7.80 (12H, m, aromatic); 7.90-8.00 (3H, m, aromatic); 8.10-8.20 (2H, d, aromatic).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12.C1(C)C=CC=CC=1.[NH3:29].CO.[Cl-].[Na+]>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:7]([C:8]([NH2:29])=[O:9])=[CH:6][N:5]=[C:4]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:3]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C(=O)O)cnc21
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C(N)=O)cnc21
Reaction time: 1 h
Yield: 96.2 %

Procedure:
4-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (480 mg, 1.47 mmol) in thionyl chloride (3 mL) was stirred at room temperature for 2 hours. After addition of toluene, the reaction mixture was concentrated under reduced pressure, and after addition of toluene, concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL), and ammonia-methanol solution (7.0 M, 1.0 mL, 7.0 mmol) was added dropwise, and the resulting reaction mixture was stirred for 1 hour. After addition of saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (461 mg, yield 96%).
Reaction SMILES: [CH2:1]([N:3]([CH2:46][CH3:47])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=[O:5])[CH3:2].N1(C(C2C=CC=CC=2S)=O)CCCC[CH2:50][CH2:49]1>>[N:3]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:14]2[C@H:15]([CH3:45])[C@@H:16]3[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]3[C:18]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])=[O:5])[CH2:46][CH2:47][CH2:50][CH2:49][CH2:2][CH2:1]1
Reactant: O=C(c1ccccc1S)N1CCCCCC1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3C(=O)N3CCCCCC3)[C@H](C)[C@H]12
Yield: 95 %

Procedure:
Following a procedure similar to that described in Example 18, but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 2-(1-perhydroazepinylcarbonyl)phenylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 95%. This compound was found to be the same as title compound prepared as described in Example 36 and had the same physicochemical properties.
Reaction SMILES: [Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH2:15])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH3:29])=[O:27].CC1C=CC(S(OC)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:13]2[CH2:12][CH:11]([CH2:14][NH:15][C:26](=[O:27])[O:28][CH3:29])[O:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Reactant: COC(=O)Cl
Agent: COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCC1Cc2c(Cl)cc3c(c2O1)CCC3
Yield: 92.6 %

Procedure:
Treatment of (±)-1-(4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine hydrochloric salt (0.60 g, 2.3 mmol) with diisopropylethylamine (0.89 g, 6.9 mmol) and methyl chloroformate (0.44 g, 4.6 mmol) generally according to the procedure described for Intermediate 7 provided 0.6 g of (±)-methyl (4-chloro-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methylcarbamate as white solid. mp 139-141° C.; Anal. calcd. for C14H16ClNO3: C, 59.68; H, 5.72; N, 4.97. Found: C, 58.99; H, 5.72; N, 4.86.
Reaction SMILES: Cl.Cl[CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])[CH3:4].[NH2:26][C@H:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].N[C@@H](CCN)C(O)=O>>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([NH:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([CH:3]([NH:26][C@H:27]4[CH2:31][CH2:30][NH:29][C:28]4=[O:32])[CH3:4])[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N[C@H]1CCNC1=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)Cl
Agent: Cl
Agent: NCC[C@H](N)C(=O)O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)N[C@H]1CCNC1=O

Procedure:
6-(1-Chloroethyl)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine hydrochloride (Described in Example 91) was coupled with (3S)-3-aminopyrrolidin-2-one (prepared from (2S)-2,4-diaminobutanoic acid according to the method in Synthesis 1978, 614) using an analogous method to that described for the equivalent step in Example 62 to give (3S)-3-[(1-{4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethyl)amino]pyrrolidin-2-one as a 1:1 mixture of diastereoisomers; 1H NMR Spectrum: (DMSO d6) 1.42 and 1.46 (both d, 1.5H); 1.71 and 1.81 (both m, 0.5H); 2.09 and 2.31 (both m, 0.5H); 3.00 (t, 0.5H); 3.11 (m, 1.5H); 3.23 (t, 1H); 4.03 (s, 3H); 4.27 and 4.52 (both m, 0.5H); 7.25 and 7.27 (both s, 0.5H); 7.34 (m, 1H); 7.53 (m, 1H); 7.61 (m, 1H); 7.74 and 7.77 (both s, 0.5H); 8.49 (m, 2H); 9.79 and 9.88 (both s, 0.5H); Mass Spectrum: (M+H)+ 430.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]3[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]3[CH:12]=[C:13]4[C:18](=[C:19]([CH3:21])[CH:20]=3)[N:17]=[CH:16][C:15]([C:22]([NH2:24])=[O:23])=[C:14]4[NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)(=[O:10])=[O:9])[CH:3]=2)=[CH:38][CH:37]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(Br)c4)cc23)c1
Reactant: OCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a suspension of Intermediate 62 (0.95 mmol) and 4-(hydroxymethyl)phenylboronic acid (290 mg, 1.90 mmol) in DME (10 mL) at room temperature was added 2 M Na2CO3 (1.4 mL, 2.85 mmol) and PdCl2(PPh3)2 (33 mg, 0.005 mmol). The reaction mixture was stirred at reflux for 2 h and then cooled to room temperature. After the addition of 60 mL of chloroform, a white precipitate formed which was collected by filtration. The crude product was purified by flash column chromatography (0-15% MeOH in dichloromethane) to give the title compound (357 mg, 68% for 3 steps). ES/MS calcd. for C31H28N3O5S+ 554.2. Found m/z=554.3 (M+H)+.
Reaction SMILES: C[C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])(C)N1.C(=O)=O.[Li]CCCC.[Cl:19][C:20]1[C:21]([Cl:29])=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].C(=O)C1C=CC=CC=1>C1COCC1>[Cl:29][C:21]1[N:22]=[CH:23][C:24]2[C:25](=[O:27])[O:26][CH:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:10]=3)[C:28]=2[C:20]=1[Cl:19]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: O=C1OC(c2ccccc2)c2c1cnc(Cl)c2Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 2,2,6,6-tetramethyl-piperidine (7.5 ml, 44 mmol) in a 250 ml round bottomed flask equipped with a magnetic stirrer, is put under argon atmosphere and 30 ml of dry THF is added. The reaction mixture is cooled to −50° C. by adding a controlled amount of dry ice to an acetone bath. The cooled reaction mixture is treated dropwise with nBuLi solution (16.3 mL of a 2.5 M solution in hexanes, 40 mmol) and the reaction is let stir at that −50° C. for 0.5 h. A solution of 5,6-dichloro-nicotinic acid, (3.7 g, 18.5 mmol) in THF (15 mL) is added dropwise to the reaction at −50° C. The reaction is stirred at −50° C. for 0.5 h. The reaction mixture is treated with benzaldehyde (2.5 ml, 24 mmol) dropwise at −50° C. The reaction is stirred at −50° C. for 2 h and warmed to room temperature overnight. The reaction mixture is concentrated to remove solvent and water and ether are added. The aqueous layer is extracted with ether (6×50 ml). The aqueous phase is treated with 1N HCl, until the pH of aqueous layer is ˜6 and is then extracted with ether (3×40 mL.) The aqueous solution is treated with 1N HCl solution until the pH ˜2 and solution is heated at 100° C. overnight. On cooling a white precipitate appeared. The precipitate is filtered off and washed with bicarbonate and air-dried to give the title compound (4.6 g, 89%) as a white solid.