Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[C:13]([Br:15])(C)[CH:12]=[CH:11][CH:10]=[C:3]1[C:4](N(OC)C)=[O:5].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([Mg]Br)=[CH:20][CH:19]=1>>[Br:15][C:13]1[C:2]([F:1])=[C:3]([C:4]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[O:5])[CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)C1=CC=CC(C)(Br)C1F
Product: COc1ccc(C(=O)c2cccc(Br)c2F)cc1

Procedure:
Prepared according to Method A step B from 2-fluoro-3-bromo-N-methoxy-N,3-dimethyl-benzamide (8.00 g, 30.5 mmol) and 4-methoxyphenylmagnesium bromide (65 mL, 0.5 M in THF) to give 3.12 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:21])[NH:12][C:13]4[N:14]([N:16]=[C:17]([S:19][CH3:20])[N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2].I([O-])(=O)(=O)=[O:23].[Na+]>>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]3[C:11](=[O:21])[NH:12][C:13]4[N:14]([N:16]=[C:17]([S:19]([CH3:20])=[O:23])[N:18]=4)[C:15]=3[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c1ncc1c(=O)[nH]c3nc(SC)nn3c12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Product: CCn1ncc2c1ncc1c(=O)[nH]c3nc(S(C)=O)nn3c12

Procedure:
3.01 g. of 8-ethyl-2-methylthio-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one obtained in Example 10a are oxidized with 2.2 g. of sodium metaperiodate in aqueous alcohol for 7 days at room temperature. The precipitate of 8-ethyl-2-methylsulfinyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one is filtered off, washed with water and recrystallized from dimethylformamide, yield 2.8 g. (88%); m.p. >300°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:4]([O:14]C)[CH:3]=1.C[S-].[Na+].Cl>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Br)cc(OC)c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC[C@H](C)Oc1cc(O)cc(Br)c1
Temperature: 130 °C
Yield: 94.9 %

Procedure:
1-Bromo-3-methoxy-5-[(1S)-2-methoxy-1-methylethoxy]benzene (9.21 g, 33.5 mmol) synthesized in Example (38a) was dissolved in 1-methyl-2-pyrrolidone (100 mL), and sodium thiomethoxide (2.75 g, 37.3 mmol) was added, followed by stirring at 130° C. for 3 for hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, 2N hydrochloric acid (500 mL) was added, and extraction was carried out with diethyl ether (300 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-25%) to afford the desired compound (8.30 g, yield 95%) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH3:20])=[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.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:41][S:38]([C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=2)(=[O:39])=[O:40])=[O:26])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: COc1cccc(S(N)(=O)=O)c1
Product: COc1cccc(S(=O)(=O)NC(=O)c2ccc([C@H](C)NC(=O)c3cc(Cl)cnc3Oc3ccc(F)cc3)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 3-methoxybenzenesulfonamide: 1H-NMR (CDCl3) δ 8.51 (1H, d, J=2.8 Hz), 8.13 (1H, d, J=2.8 Hz), 8.09 (1H, d, J=7.0 Hz), 7.73 (2H, d, J=8.4 Hz), 7.70–7.64 (2H, m), 7.49–7.39 (3H, m), 7.21–7.08 (5H, m), 5.37–5.25 (1H, m), 3.88 (3H, s), 1.56 (3H, d, J=6.8 Hz); MS (ESI) m/z 584 (M+H)+, 582 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH2:15])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[C:21]([C:22](O)=[O:23])=[C:20]([CH3:25])[O:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][NH:15][C:22]([C:21]2[C:17]([CH3:16])=[N:18][O:19][C:20]=2[CH3:25])=[O:23])[CH2:12][C@H:11]2[C@@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1noc(C)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1[C@H](CN)C[C@@H]2C[C@@H]21
Product: Cc1noc(C)c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C

Procedure:
prepared by reaction of (1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester with 3,5-dimethyl-isoxazole-4-carboxylic acid. LC-MS (acidic): tR=0.93 min; [M+H]+=336.2. 1H-NMR (CDCl3): δ=0.51 (bs, 1H); 0.81-0.87 (m, 1H); 1.49 (s, 9H); 1.50-1.56 (m, 1H); 1.74 (bd, J=13.5 Hz, 1H); 2.47 (s, 3H); 2.52-2.62 (m, 1H); 2.64 (s, 3H); 3.05-3.11 (m, 1H); 3.57-3.65 (m, 2H); 4.32-4.40 (m, 1H); 7.95 (bs, 1H).
Reaction SMILES: O[CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:41]I>C(Cl)(Cl)Cl>[I:41][CH2:2][C@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15]
Reactant: C[C@@H](CO)CN1C(=O)COc2ccccc21
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](CI)CN1C(=O)COc2ccccc21
Yield: 20 %

Procedure:
Crude (R)-4-(3-hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM40-37) (1.040 g), triphenylphosphine (0.99 g, 3.77 mmol), imidazole (0.32 g, 4.71 mmol) and iodine (1.43 g, 5.65 mmol) in CHCl3 (30 mL) were reacted according to GP4 to give the crude title compound (108LM46-43) (0.312 g).
Reaction SMILES: CNC(O[CH:6]([CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][NH2:8])=O.[Cl:32][CH2:33][CH2:34][CH2:35][S:36](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:38])=[O:37]>>[Cl:32][CH2:33][CH2:34][CH2:35][S:36]([NH:8][CH2:7][CH:6]([NH:12][C:11]([O:10][CH3:9])=[O:31])[CH2:9][O:10][C:11](=[O:31])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=[O:37])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC(=O)NC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OC

Procedure:
2-Methoxycarbonylamino-3-octadecylcarbamoyloxypropylamine IV e1 is allowed to react and worked up by the same procedure as described in (4). mp. 99°-101° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13](N)=[O:14].Cl.[OH-:17].[Na+]>>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([OH:14])=[O:17]
Reactant: [OH-]
Reactant: NC(=O)CC1Nc2ccccc2NC1=O
Agent: Cl
Agent: [Na+]
Product: O=C(O)CC1Nc2ccccc2NC1=O

Procedure:
2-(3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetamide (22 g, 0.11 mol) was dissolved in 10% NaOH (600 mL) and was heated under reflux for 3 hours. The mixture was cooled down via an ice-bath and was acidified with pre-cooled 10% HCl to pH˜6. The solvent was concentrated and the resulting precipitate was isolated via filtration to give a gray solid as the title product: 1H NMR (DMSO-d6) δ=12.35 (bs, 1H), 10.25 (bs, 1H), 6.74–6.68 (m, 3H), 6.61–6.58 (m, 1H), 5.91 (bs, 1H), 4.08–4.04 (m, 1H), 2.69 (dd, 1H, J=5.1, 16.2 Hz), 2.51 (dd, 1H, J=6.9, 16.2 Hz)
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O>C1COCC1>[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccco1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC=Cc1ccco1
Yield: 60.5 %

Procedure:
This compound was synthesized from 7-carboxyheptyltriphenylphosphonium bromide (9.71 g, 20 mmol) and 2-furaldehyde (1.92 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation yielded the product (2.69 g, 61%) as a pale yellow oil (bp 136-139° C./0.05 torr). IR: 3500-2500, 1730, 710 cm-1 ; 1H-NMR: 1.40 (m, 8H), 2.35 (m, 4H), 5.55 (m, 1H), 6.30 (m, 3H), 7.35 (s, 1H), 11.40 (bs, 1H). Anal. Calcd. for C13H18O3 : C, 70.25, H, 8.16%; Found: C, 69.98, H, 8.26%. Z:E=79:21.
Reaction SMILES: [CH3:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](O)[C:5]=2[N:6]=1.[CH3:26][N:27]1[CH:34]=[CH:33][C:31](=[O:32])[NH:30][C:28]1=[O:29]>FC(F)(F)C(O)=O>[CH3:26][N:27]1[CH:34]=[C:33]([CH:7]2[C:5]3[N:6]=[C:2]([CH3:1])[NH:3][C:4]=3[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)[C:31](=[O:32])[NH:30][C:28]1=[O:29]
Reactant: COc1ccc(Cn2c(C)nc3c2C=Cc2ccccc2C3O)cc1
Reactant: Cn1ccc(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c([nH]1)C=Cc1ccccc1C2c1cn(C)c(=O)[nH]c1=O
Reaction time: 120 h

Procedure:
A stirred solution of the product from step (iii) (0.819 g) in trifluoroacetic acid (20 ml) was heated at reflux for 1 h. 1-Methyluracil (0.311 g) was added and the reflux continued for 5 days. The solvent was evaporated under reduced pressure. The residue was purified by chromatography eluting with 10% methanol in dichloromethane to give the subtitle product as pale green glass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([O-:21])=O)=[CH:17][N:16]=1)[CH2:7][CH2:6]2.[NH2:24][OH:25].[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][OH:25])=[O:21])=[CH:17][N:16]=1)[CH2:7][CH2:6]2
Reactant: NO
Reactant: COc1cc2c(cc1OC)CN(c1ccc(C(=O)[O-])cn1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(c1ccc(C(=O)NO)cn1)CC2
Reaction time: 72 h

Procedure:
A solution of 6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)nicotinate (12 mg) in dioxane (0.8 mL) was treated with 50% aqueous hydroxylamine (0.2 mL). After 10 minutes the reaction was treated with 1N sodium hydroxide (0.06 mL) and the solution stirred for 72 hours. The reaction was quenched with 1N hydrochloric acid (0.06 mL) and the solvent was evaporated. The residue was purified by preparative hplc and the pure samples freeze dried to give 6-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-hydroxynicotinamide as a yellow solid (7.9 mg), m/e=330 (M+1). 1H NMR (DMSOd6) ppm: 2.8 (2H, m), 3.72 (6H, s) 3.9 (2H, m), 4.7 (2H, s), 6.76 (1H, s), 6.83 (1H, s), 6.9 (1H, d), 7.9 (1H, m), 8.55 (1H, s), 11 (1H, bs).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>O>[CH2:15]([S:22][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: SCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 92.1 %

Procedure:
In a similar fashion using route 38 general procedure 92, 1-chloro-4-methanesulfonyl-2-nitrobenzene (750 mg, 3.19 mmol), benzylmercaptan (450 ml, 3.82 mmol), Na2CO3 (439 mg, 4.14 mmol) and EtOH:water (25 ml: 18 ml) at 90° C. for 4 h gave the title compound (950 mg, 92%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [N+](=[C:3]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH3:16][OH:17]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH:3]([O:17][CH3:16])[C:4]([O:6][CH3:7])=[O:5])=[CH:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)=[N+]=[N-]
Reactant: CO
Agent: [Rh]
Solvent: CC(=O)O
Product: COC(=O)C(Cc1ccc(O)cc1)OC
Reaction time: 15 h

Procedure:
A solution of methyl 2-diazo-3-(4hydroxyphenyl)propanoate (cf Tetrahedron Lett., 1971,4495) (8.58 g) in methanol (120 mL) was added over 10 minutes to a mixture of rhodium (II) acetate dimer (0.18 g) in methanol (50 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was heated at reflux for 5 hrs, allowed to stand at room temperature for 15 hrs, then concentrated in vacuo. The residue was dissolved in ethyl acetate (500 mL), washed with water (3×300 mL) and brine (500 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with a gradient of 4% ethyl acetate to 6% ethyl acetate in dichloromethane as eluent to afford the title compound, mp 61-3° C.
Reaction SMILES: [Li+].[OH-].[N:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])(=[O:11])=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl>O1CCCC1.O.C(OCC)(=O)C>[N:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:16]([CH:21]=2)[C:17]([OH:19])=[O:18])(=[O:11])=[O:10])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 50 °C

Procedure:
LiOH (23.25 mg, 0.97 mmol) was added to a stirred solution of methyl 5-(4-morpholinylsulfonyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 65; 380 mg, 0.97 mmol) in a mixture of tetrahydrofuran and water (3:1, 40 ml). The mixture was heated at 50° C. for 6 h, and then diluted with ethyl acetate (50 m). 10% Aqueous HCl was added to the mixture to adjust pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to yield the title compound as a white solid. 250 mg.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5]([C:7](=[N:30][OH:31])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([S:23][C:24]2[S:25][C:26]([NH2:29])=[N:27][N:28]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[Na].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].O>CN(C=O)C>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:40][CH2:41][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[S:23][C:24]1[S:25][C:26]([NH2:29])=[N:27][N:28]=1)[C@H:11]([NH:10][C:8](=[O:9])[C:7]([C:5]1[N:6]=[C:2]([NH2:1])[S:3][C:4]=1[Cl:32])=[N:30][OH:31])[C:18]2=[O:19])=[O:22])=[O:39]
Reactant: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NO)c4nc(N)sc4Cl)C3SC2)s1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(Sc2nnc(N)s2)CSC2[C@H](NC(=O)C(=NO)c3nc(N)sc3Cl)C(=O)N12
Reaction time: 1 h

Procedure:
To a stirring solution of (7R)-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (65 mg, 0.117 mmol) in DMF (0.3 mL) under nitrogen was added iodomethyl pivalate (31 mg, 0.128 mmol). After 1 h, water was added dropwise, and the precipitated product was removed by filtration to give 60.9 mg of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18](I)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)#[CH:25].C(NCC)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:22][CH3:23])=[C:18]([C:25]#[C:24][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C#Cc1ccccn1
Reactant: COc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2cc1I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2cc1C#Cc1ccccn1

Procedure:
The title compound was synthesized according to the method of Example 2 using (1H-indol-5-yl)-(6-iodo-7-methoxy-quinazolin-4-yl)-amine (135 mg, 0.486 mmol), 2-ethynyl-pyridine (185 mg, 1.45 mmol) and diethylamine (605 mg, 8.27 mmol) in 2 mL., of DMF.
Reaction SMILES: [Na].CC(C)(C)C([O:6][CH2:7][C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([NH:17][C:18]([C:20]1[N:21]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[C:22]3[C:27]([CH:28]=1)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=3)=[O:19])=[CH:12][N:11]=2)=O>CO>[OH:6][CH2:7][C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([NH:17][C:18]([C:20]1[N:21]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[C:22]3[C:27]([CH:28]=1)=[CH:26][C:25]([F:29])=[CH:24][CH:23]=3)=[O:19])=[CH:12][N:11]=2
Reactant: CC(C)(C)C(=O)OCc1nc2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cnc2s1
Agent: [Na]
Solvent: CO
Product: O=C(Nc1cnc2sc(CO)nc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
50 mg (2.03 mmol) of sodium are added to 8 mL of methanol with stirring at 20° C. After 15 minutes, a solution of 0.15 g (0.28 mmol) of [6-[[[5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indol-2-yl]carbonyl]amino]thiazolo[5,4-b]pyrid-2-yl]methyl 2,2-dimethylpropanoate (Compound 13), prepared in step 4.3, in 16 mL of methanol is added. Stirring is continued for 15 minutes at 20° C., and the reaction mixture is then concentrated under reduced pressure and taken up in 200 mL of molar ammonium chloride solution. The aqueous phase is extracted three times with 50 mL of ethyl acetate. The organic phases are combined, washed with 50 mL of saturated sodium chloride solution and then dried over sodium sulfate and concentrated under reduced pressure. The product thus obtained is purified on a column of silica, eluting with a mixture of dichloromethane and methanol. 70 mg of the expected product are thus isolated.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([F:45])[CH:34]=1.COCCS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:37](=[O:39])[C:36]2[CH:40]=[C:41]([CH:42]3[CH2:43][CH2:44]3)[C:33]([O:32][C@H:26]3[CH2:27][C@H:28]4[CH2:31][C@@H:25]3[CH2:30][CH2:29]4)=[CH:34][C:35]=2[F:45])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 56 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with azetidine-1-sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.080 g, 56%): 1H NMR (300 MHz, DMSO-d6) δ 11.54 (br s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.85 (d, J=13.1 Hz, 1H), 4.42-4.36 (m, 1H), 4.01 (t, J=7.6 Hz, 4H), 2.39-2.34 (m, 1H), 2.30-2.45 (m, 1H), 2.19-2.06 (m, 2H), 2.01-1.90 (m, 1H), 1.87-1.77 (m, 1H), 1.60-1.32 (m, 4H), 1.26-1.04 (m, 3H), 0.88-0.80 (m, 2H), 0.68-0.59 (m, 2H); MS (ES−) m/z 409.2 (M+1).
Reaction SMILES: C(N([CH2:17][C:18](O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([O-])(=O)CCCCCCC/C=C\CCCCCCCC.[K+].[Cl-].[K+].C=O.[C:46]1([S:56](O)(=O)=O)[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=1.[Na]>O>[CH2:46]([SH:56])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:17][CH3:18]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: O=S(=O)(O)c1cccc2ccccc12
Agent: C=O
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Cl-]
Solvent: O
Product: CCCCCCCCCCCCS

Procedure:
A solution of 1.16 g polyethylene oxide (prepared according to the teaching of DE 1 213 984) and 0.06 g ethylenediamine tetraacetic acid in 2.54 g deionized water is added, followed by 46.0 g deionized water. After 3 hours a solution of 4.12 g potassium oleate, 0.03 g potassium chloride and 0.36 g naphthalene sulfonic acid formaldehyde condensate, sodium salt in 21.7 g deionized water, followed by 46.0 g of deionized water. Finally the latex has a solids content of ca. 30%.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[CH3:18]>CCO.[Pd]>[CH3:18][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][C:9]=1[N:5]1[CH2:4][C@@H:3]2[CH2:8][C@H:6]1[CH2:7][N:2]2[CH3:1])[NH2:15]
Reactant: Cc1cc([N+](=O)[O-])ccc1N1C[C@@H]2C[C@H]1CN2C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1N1C[C@@H]2C[C@H]1CN2C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
2-[(1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-5-nitrotoluene (14.2 g), as prepared above in Paragraph D, was dissolved in EtOH (50 mL), transferred to a Parr hydrogenation flask. Pd/C (1.5 g) was introduced to above flask and subjected to hydrogenation at 30 psi for 2 h. The reaction mixture was filtered through Celite and the filter cake was washed further with EtOH (300 mL). Concentration of the filtrate provided 3-Methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]aniline as a white-tan solid (11.7 g, 86%); 1H NMR (DMSO-d6): δ 6.58 (d, 1H, J=8.8 Hz), 6.34 (s, 1H), 6.27 (d, 1H, J=8.8 Hz), 4.46 (s, 2H), 3.61 (s, 1H), 3.24 (s, 1H), 3.16 (d, 1H, J=9.3 Hz), 2.93 (dd, 1H, J=1.8 and 9.3 Hz), 2.61 (qt, 2H, J=9.3 Hz), 2.26 (s, 3H), 2.05 (s, 3H), 1.70 (d, 1H, J=9.1 Hz), 1.63 (d, 1H, J=9.1 Hz). LCMS: purity: 97%; MS (m/e): 218 (MH+).