Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[S:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].[N:25]1C=CC=CC=1>>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:3]2[C:4]([NH2:25])=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=2[S:21]([CH3:20])(=[O:23])=[O:22])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1Sc1ccc(Cl)cc1
Reactant: c1ccncc1
Product: CS(=O)(=O)c1ccc(S(N)(=O)=O)c(N)c1Sc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
4-Amino-3-(4-chlorophenylthio)-benzenesulphonamide (0.43 g; 1.37 mmol) was dissolved in pyridine (10 ml) and at 0° C. methanesulphonic acid chloride (4.7 g; 41.0 mmol) was added dropwise. The solution came up to ambient temperature overnight, was then poured onto water and extracted with CH2Cl2. The solvent was evaporated off and the residue was stirred in dioxan (10 ml)/2N aqueous NaOH (10 ml). After acidifying with 2N HC1, the mixture was extracted with ethyl acetate, dried over MgSO4 and evaporated down. The residue was recrystallised from CH2Cl2. Yield: 0.28 g=52% 13C (100 MHz, DMSO-d6) δ 141.50, 140.23, 133.03, 132.82, 132.73, 129.79, 129.78, 129.46, 126.16, 123.90, 41.03
Reaction SMILES: [N:1]1([CH2:7][CH2:8]O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.S(Cl)([Cl:12])=O>C1C=CC=CC=1>[ClH:12].[Cl:12][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cl
Product: ClCCN1CCOCC1
Yield: 151.8 %

Procedure:
In 2 l of benzene was dissolved 623 g of morpholine ethanol. The solution was stirred while maintaining its temperature below 35° C. with ice-cooling, followed by dropwise addition of 735 g of thionyl chloride in 500 ml of benzene. Upon completion of the dropping, the resultant mixture was refluxed with stirring for 4 hours. After cooling, the crystalline precipitate was collected to give 872.4 g (yield: 98.7%) of chloroethylmorpholine hydrochloride having a melting point of 180°-182° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:23](N=P(N(C)C)(N(C)C)N(C)C)(C)([CH3:25])[CH3:24].C(Br)C=C>ClCCl.Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([O:19][CH2:25][CH:23]=[CH2:24])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)P(=NC(C)(C)C)(N(C)C)N(C)C
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Agent: Cl
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Temperature: 20 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N′″-tert-butyl-N,N, N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016 g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20° C. The product mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, observed: 420.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)[CH:17]([C:36](O)=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH3:39][N:40]([CH3:44])[CH2:41][CH2:42][NH2:43]>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][C:19](=[O:21])[N:18]([N:22]([CH3:35])[CH:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)[CH2:25][CH2:24]3)[CH:17]([C:36]([NH:43][CH2:42][CH2:41][N:40]([CH3:44])[CH3:39])=[O:37])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1C(=O)O
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC(=O)N1N(C)C1CCN(c2ccncc2)CC1
Product: Cl

Procedure:
Similarly to Example 116 and using 4-[(6-chloro-2-naphthyl)sulfonyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinecarboxylic acid (0.18 g) obtained in Example 110 and N,N-dimethyl ethylenediamine (0.035 ml), the title compound (0.17 g) was obtained as a pale yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:24])[NH:18][NH:19][C:20]=2[CH:21]([CH3:23])[CH3:22])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(OC(C(C)(C)COC1C=CC(CC2C(=O)NNC=2C(C)C)=CC=1)=O)C1C=CC=CC=1.CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([O:24][C@@H:34]3[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]3[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:18][NH:19][C:20]=2[CH:21]([CH3:22])[CH3:23])=[C:11]([CH3:25])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCC(C)(C)C(=O)OCc2ccccc2)cc1
Product: Cc1cc(OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 12 using 4-[(4-benzyloxy-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (Kunz, H.; Harreus, A. Liebigs Ann. Chem. 1982, 41-48 Velarde, S.; Urbina, J.; Pena, M. R. J. Org. Chem. 1996, 61, 9541-9545) instead of 4-{[4-(2-benzyloxycarbonyl-2-methylpropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38]>>[Cl:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7])=[O:38]
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: O=C(O)c1cccc(Cl)c1
Product: CS(=O)(=O)N(CCCNC(=O)c1cccc(Cl)c1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with 3-chlorobenzoic acid following procedure K. LC-MS showed the product had the expected M+H+ of 594. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (d, 1H) 7.82 (s, 1H) 7.7 (d, 1H) 7.55 (d, 2H) 7.2 (m, 2H), 7.3 (m, 2H), 6.9 (m, 2H), 6.8 (d, 2H), 6.71 (d, 1H), 6.5 (d, 2H), δ 4.2 (s, 2H), 3.49 (t, 2H), 3.2 (d, 2H), 3.5 (t, 2H), δ 2.6 (s, 3H), δ 1.4 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:18][C:19]1[C:20]([NH:28][C@@H:29]2[CH2:34][O:33][CH:32]([CH2:35][C:36]#[N:37])[CH2:31][CH2:30]2)=[C:21]2[S:27][CH:26]=[CH:25][C:22]2=[N:23][CH:24]=1>C1COCC1.C(O)C>[OH:1][CH2:2][C:3]1[N:28]([C@@H:29]2[CH2:34][O:33][C@@H:32]([CH2:35][C:36]#[N:37])[CH2:31][CH2:30]2)[C:20]2=[C:21]3[S:27][CH:26]=[CH:25][C:22]3=[N:23][CH:24]=[C:19]2[N:18]=1
Reactant: N#CCC1CC[C@H](Nc2c(N)cnc3ccsc23)CO1
Reactant: NC(=O)CO
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC[C@H]1CC[C@H](n2c(CO)nc3cnc4ccsc4c32)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A mixture of 2-hydroxyacetamide (93.3 mg, 1.24 mmol) and triethyloxonium tetrafluoroborate (234 mg, 1.23 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.7 mL) and added to a suspension of {(5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}acetonitrile (101 mg, 0.350 mmol) in ethanol (2.6 mL). The reaction mixture was stirred at 80° C. for 1 h, and then cooled to room temperature. The solid was filtered off. The filtrate was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (40 mg, 35%). LCMS calculated for C16H17N4O2S (M+H)+: m/z=329.1. Found: 329.1. 1H NMR (DMSO-d6, 500 MHz) δ 8.98 (s, 1H), 8.04 (d, J=5.5 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 5.89 (s, 1H), 4.92 (m, 1H), 4.87 (s, 2H), 4.28 (m, 1H), 4.18-4.11 (m, 1H), 3.98 (m, 1H), 2.95 (dd, J=17.0, 4.3 Hz, 1H), 2.83 (dd, J=17.0, 6.6 Hz, 1H), 2.64 (m, 1H), 2.49 (m, 1H), 2.22 (m, 1H), 2.06 (m, 1H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:11]=[CH:12][C:13](C2C=CC=C(C3N4C=CC(C(O)(C)C)=NC4=NC=3)N=2)=[C:14]([CH:17]=1)[C:15]#[N:16]>>[Br:8][C:4]1[N:3]=[C:2]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:17][C:14]=2[C:15]#[N:16])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(O)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)n3)cnc2n1
Reactant: Brc1cccc(Br)n1
Product: N#Cc1cc(F)ccc1-c1cccc(Br)n1
Yield: 49.8 %

Procedure:
2,6-Dibromopyridine (1.17 g, 5.0 mmol) was coupled to 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (synthesised as in Example 22) (1.48 g, 6.0 mmol) as described in Example 27 to afford 2-(6-bromopyridin-2-yl)-5-fluorobenzonitrile (0.69 g, 50%) as a white solid: δH (400 MHz, CDCl3) 1.42 (9H, s), 6.96 (1H, d, J 7), 7.45 (1H, d, J 1), 7.72 (1H, d, J 1), 8.33 (1H, d, J 7).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28].S(=O)(=O)(O)[OH:30].O>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:18]([F:19])=[CH:17][C:16]([F:20])=[C:15]([NH:21][CH2:22][CH2:23][CH2:24][C:25]([OH:30])([CH3:26])[CH3:27])[C:11]=3[C:12](=[O:14])[CH:13]=2)=[CH:4][C:3]=1[F:28]
Reactant: O=S(=O)(O)O
Reactant: CC(C)=CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Solvent: CCO
Solvent: O
Product: CC(C)(O)CCCNc1c(F)cc(F)c2oc(-c3ccc(N)c(F)c3)cc(=O)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
16 mg (0.041 mmol) of Compound 137 obtained in Example 137 was dissolved in 3 mL of ethanol, 3 mL of 50% sulfuric acid was added and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled on ice, water was added and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with an aqueous saturated solution of sodium bicarbonate, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 14 mg of Compound 138 (yield: 84%).
Reaction SMILES: [NH:1]([C:25]([O:27]C(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:9])[CH3:7])=[O:4].Cl.O1CCOCC1.[NH:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40]C(O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[NH:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][C:25]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([N:10]1[CH2:24][CH2:23][CH2:22][C@H:11]1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:9])[CH3:7])=[O:4])=[O:27]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 85.9 %

Procedure:
Compound II (65.03 g, 0.15 mole) was deblocked with HCl/dioxane and coupled to Boc-Gly-OH (26.3 g, 0.15 mole) using EDCI with HOBt in the same manner as that described for II to give 63.2 g (yield 85.9%) of III R1f, 0.3; R2f, 0.46.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[C:24]([N+:34]([O-])=O)=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[C:12]([CH2:37][CH3:38])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:34][C:24]1[C:23]([C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][N:40]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[CH2:37][CH3:38])=[CH:27][NH:26][N:25]=1
Reactant: CCc1cc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)ccc1O[C@H]1CCCC[C@@H]1c1cn(C2CCCCO2)nc1[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(S(=O)(=O)Nc2ccncn2)ccc1O[C@H]1CCCC[C@@H]1c1c[nH]nc1N
Yield: 107.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-3-ethyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (70 mg, 0.0990 mmol) prepared in Example 89c, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (47 mg, 99%) as a white solid.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>CO.O>[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[C:9]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: Clc1cccc2cc[nH]c12
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
Potassium hydroxide (6.89 g, 0.12 mol) was dissolved in methanol (30 mL). To the solution were added 7-chloroindole (4.65 g, 0.031 mol), 4-piperidone hydrochloride hydrate (9.48 g, 0.061 mol). The mixture was stirred at reflux temperature under nitrogen for about a day, and was cooled and diluted with 50 mL of water, added dropwise. The solid was collected, washed with water and vacuum dried. Yield 5.6 g (78%) as a yellow solid. mp 197°-201° C. FDMS m/e=232 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:39])[CH:37]=[CH2:38].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:38]=[CH:37]/[C:36]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])=[C:13]([C:15]2[CH2:19][C:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:17][N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2Br)=NO1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OCc3ccccc3)ccc2/C=C/C(=O)OCc2ccccc2)=NO1
Reaction time: 48 h
Yield: 22.6 %

Procedure:
A mixture of tert-butyl 3-(5-(benzyloxy)-2-bromophenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (1.00 g), benzyl acrylate (1.484 g), palladium acetate (0.021 g), tris(2-methylphenyl)phosphine (0.084 g), triethylamine (0.765 mL), and DMF (10 mL) was stirred at 100 C for 2 days in an argon atmosphere. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (0.260 g).
Reaction SMILES: [C:1]1([C:7]([NH:20][CH:21]2[C:38](=[O:39])[N:23]3[CH:24]([C:29](=O)[NH:30][CH2:31][C:32]4[O:36][CH:35]=[CH:34][CH:33]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([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.N1C=CC=CC=1.C(Cl)(Cl)=O.[N-:50]=[N+:51]=[N-:52].CN(C)C(=[NH2+])N(C)C>C(Cl)(Cl)Cl.O>[C:1]1([C:7]([NH:20][CH:21]2[C:38](=[O:39])[N:23]3[CH:24]([C:29]4[N:30]([CH2:31][C:32]5[O:36][CH:35]=[CH:34][CH:33]=5)[N:52]=[N:51][N:50]=4)[C:25]([CH3:28])([CH3:27])[S:26][C@H:22]23)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=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
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C(=O)NCc1ccco1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnnn1Cc1ccco1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3.05 g. (5.7 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfurylcarbamoyl)penam, in 8 ml. of chloroform, at 0° C., is added 1.35 ml. (17 mmole) of pyridine, followed by 2.64 ml. of a 4.33 M solution of phosgene in chloroform. Stirring is then continued for 1 hour at 25° C. The chloroform, and excess phosgene and pyridine, are then removed by evaporation in vacuo, and the residue is redissolved in 5 ml. of chloroform. The solution is cooled to 0° C., and then 2.25 g. (14.4 mmole) of tetramethylguanidinium azide is added in several small portions. Stirring is continued for 15 minutes at ambient temperature, and then 20 ml. of chloroform, followed by 30 ml. of water, are added and the pH is adjusted to 6.5. The chloroform layer is separated off, washed with water, followed by brine, and then dried (MgSO4). Removal of the solvent by evaporation in vacuo leaves 3.37 g. of a dark-red foam. The foam is re-dissolved in a small volume of chloroform and absorbed onto a column of chromatographic silica gel. Elution of the column with chloroform, followed by evaporation of the appropriate fractions in vacuo, affords 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam. The NMR spectrum of the product (CDCl3) shows absorptions at 7.40 ppm (m, 16H), 6.40 ppm (m, 2H), 5.50 ppm (s, 2H), 5.20 ppm (s, 1H), 4.90 ppm (m, 2H), 1.60 ppm (s, 3H), and 0.80 ppm (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[CH3:13][C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])[CH3:15].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)(Cl)Cl>[C:14]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[F:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:13])[CH3:15]
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2F)CC1
Temperature: 80 °C

Procedure:
A mixture of 5 g (20 mmol) 1-Bromo-2-fluoro-4-trifluoromethyl-benzene, 4.6 g (24.7 mmol) n-Boc-piperazine, 106 mg (0.1 mmol) Tris(dibenzylideneacetone)dipalladium chloroform complex 2.77 g (28.8 mmol) sodium-t-butoxide and 144 mg (0.4 mmol) 2-(Dicyclohexylphosphino)biphenyl in 50 ml toluene was heated for 16 h at 80° C. After cooling to room temperature the mixture was treated with 15 g Isolute HM-N and all volatiles were removed under vacuum. The residue was purified on silica eluting with a gradient of heptane/EtOAc to yield after evaporation 4.54 g (63%) of the title compound as white amorphous solid; MS (m/e): 349.2 (MH+, 100%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].CCCCCC.CI>O1CCCC1>[CH3:21][C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13][CH2:14][CH2:15][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[CH2:11]1
Reactant: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(C)CCCN(S(=O)(=O)c2ccccc2)C1
Yield: 40 %

Procedure:
At r.t., to the solution of ethyl 1-(phenylsulfonyl)piperidine-3-carboxylate (0.50 g, 2.0 mmol) in tetrahydrofuran (5.0 mL), was slowly added 1.0 M of lithium hexamethyldisilazide in hexane (2.5 mL, 2.5 mmol) with stirring. After stirring for 30 min, to the mixture was added methyl iodide (157 ul, 2.5 mmol). The mixture was stirred at r.t. overnight and was quenched with 10% citric acid, then extracted with ethyl acetate. The extract was washed with water, sat'd sodium bicarbonate solution, water, and brine, successively. The extract was then dried over sodium sulfate (anhydrous). After filtration, the filtrate was concentrated to yield 200 mg (40%) of ethyl 3-methyl-1-(phenylsulfonyl)piperidine-3-carboxylate.
Reaction SMILES: [CH:1](N(C(C)C)CC)(C)[CH3:2].CN(C(ON1N=[N:25][C:20]2[CH:21]=[CH:22][CH:23]=[N:24][C:19]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.C1COCC1.CN(C=O)C.C(Cl)Cl>[N:24]1[C:19]2[CH:1]=[CH:2][CH:22]=[CH:21][C:20]=2[NH:25][CH:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
General working instructions 14 (GWI-14): To a solution of (ACI) (1.0 eq.) in THF was added diisopropyl ethylamine (4.0 eq.) at 0° C. followed by HATU (1.5 eq.). The resultant reaction mixture was allowed to stir at room temperature for 15 min. It was again cooled to 0° C. and a solution of the amine (1.3 eq.) in THF-DMF (3:1) was added. The reaction mixture was allowed to stir at room temperature for 16 h. The mixture was then diluted with methylene chloride, washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and finally with brine. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give the crude product which was purified by neutral alumina column chromatography to obtain desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O1CCCC1.[Br:16]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:16][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[NH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2cc[nH]c12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ncnc2c(Br)c[nH]c12
Reaction time: 1 h

Procedure:
To 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg), tetrahydrofuran (5 mL) was added, and N-bromosuccinimide (116 mg) was further added thereto, followed by stirring for 1 hour. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.