Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=O)[C:26]([C:32]3[CH:33]=[N:34][N:35]([CH2:38][C:39]4([O:47][CH3:48])[CH2:44][CH2:43][CH2:42][C:41]([CH3:46])([CH3:45])[CH2:40]4)[C:36]=3[CH3:37])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:49][S:50]([NH2:53])(=[O:52])=[O:51].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[CH:24]=[CH:25][C:26]([C:32]3[CH:33]=[N:34][N:35]([CH2:38][C:39]4([O:47][CH3:48])[CH2:44][CH2:43][CH2:42][C:41]([CH3:45])([CH3:46])[CH2:40]4)[C:36]=3[CH3:37])=[C:27]([C:29](=[O:31])[NH:53][S:50]([CH3:49])(=[O:52])=[O:51])[N:28]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC1(Cn2ncc(-c3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2C)CCCC(C)(C)C1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC1(Cn2ncc(-c3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)NS(C)(=O)=O)c2C)CCCC(C)(C)C1

Procedure:
A solution of EXAMPLE 157E (0.051 g), methanesulfonamide (0.015 g), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride.HCl (0.037 g) and 4-dimethylaminopyridine (0.019 g) were stirred together in dichloromethane (1 mL) at room temperature overnight. The reaction mixture was loaded onto silica gel and eluted using a gradient of 0.5% to 3.25% methanol/dichloromethane to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.84 (s, 1H), 11.81 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56-7.41 (m, 3H), 7.41-7.32 (m, 2H), 7.29 (s, 1H), 7.00 (d, 1H), 4.96 (s, 2H), 4.00 (d, 2H), 3.93 (t, 2H), 3.16 (s, 3H), 3.11 (s, 3H), 3.03 (t, 2H), 2.13 (s, 3H), 1.71 (d, 1H), 1.58-1.00 (m, 7H), 0.96 (s, 3H), 0.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([F:9])[F:8])[N:6]=1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[F:8][CH:7]([F:9])[N:5]1[N:4]=[N:3][C:2]([NH:1][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6]1
Reactant: Nc1nnn(C(F)F)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: O=C(Nc1nnn(C(F)F)n1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 168-169° and MS: (neg. ions): m/e=342.0 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-difluoromethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20]>>[C:1]([O:6][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=COCC
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: C=C(C)C(=O)OC(C)OCC
Reaction time: 4 h
Yield: 20 %

Procedure:
To a 500-mL, 3-necked round bottomed flask equipped with a thermocouple temperature monitor, nitrogen inlet and a magnetic stirrer was added 300 mL of ethyl vinyl ether and 25.0 g (0.29 mol) of methacrylic acid. The mixture was cooled in an ice bath and 0.2 g (0.001 mol) of p-toluenesulfonic acid monohydrate was added. The flask was removed from the ice bath and stirred for 4 hours at which time the mixture was filtered through a bed of sodium carbonate and the ethyl vinyl ether removed on a rotary evaporator. The resulting oil was distilled twice from sodium carbonate at reduced pressure to yield 8.9 g (20%) of the title compound as a clear, colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44](O)=[O:45])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=2[F:43])=[N:33][C:32]=1[C:44]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)=[O:45]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1NCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1NCC1CCNCC1
Yield: 7.4 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid and HATU were reacted to give 105 as a white solid (4.4 mg, 7.4%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.36 (s, 1H), 7.67-7.36 (m, 3H), 7.27 (t, J=8.6, 2H), 4.88 (t, J=6.5, 1H), 3.63-3.55 (m, 4H), 3.01 (d, J=12.2, 2H), 2.80 (t, J=6.5, 2H), 1.76 (d, J=11.1, 2H), 1.55 (s, 1H), 1.24-1.01 (m, 2H). ESIMS m/z=448.1 (M+1)
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][CH2:5][CH:6]([NH:26][C:27](=[O:40])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:9]=1.[OH-].[K+].C1COCC1>CO.O>[C:34]1([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C@H:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:9]=2)[CH2:5][CH2:4][C:3]([OH:41])=[O:2])=[O:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)CCC(Cc1cn(CCCc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC[C@@H](Cc1cn(CCCc2ccccc2)c2ccccc12)NC(=O)CCCCCCc1ccccc1
Reaction time: 0.67 h
Yield: 75.5 %

Procedure:
To a solution of 4-(7-phenyl-heptanoylamino)-5-[1-(3-phenyl-propyl)-1H-indol-3-yl]-pentanoic acid methyl ester (95 mg, 0.172 mmol) in MeOH (0.5 mL) was added KOH (100 mg, 1.79 mmol) in water (0.5 mL). THF (1 mL) was added to homogenise the solution and the reaction was complete in 40 minutes. The solvents were removed and water added. Upon washing with ether the aqueous layer was acidified with aqueous HCl and the resultant precipitate filtered. Upon drying the solid was recrystallised from THF/Et2O to afford the title compound (70 mg, 76%), mp 100-101.5° C. 1H NMR (DMSO-d6) δ 7.64-7.59 (2H, m), 7.35-7.08 (12H, m), 7.03-6.98 (1H, m), 4.10 (2H, t, J=6.59 Hz), 4.04 (1H, br s), 2.84 (1H, dd, J=6.65, 14.39 Hz), 2.78 (1H, dd, J=6.45, 14.39 Hz), 2.55-2.49 (4H, m), 2.34-2.12 (2H, m), 2.05-2.00 (4H, m), 1.86-1.75 (1H, m), 1.66-1.44 (5H, m), 1.21 (4H, m), 13C NMR (DMSO-d6) □ 174.4, 171.9, 142.3, 141.3, 135.9, 128.3, 128.2, 128.0, 126.5, 125.8, 125.5, 120.9, 118.9, 118.3, 117.9, 110.9, 109.5, 35.6, 35.1, 32.4, 31.5, 30.9, 30.7, 30.5, 29.2, 28.5, 28. 5, 25.3. ISMS: 539 (M+H).
Reaction SMILES: [OH:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(C(C)C)CC)(C)C.[Cl:37][CH2:38][C:39](Cl)=[O:40].C(OCC)(=O)C>O1CCCC1>[Cl:37][CH2:38][C:39]([N:8]1[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH:3]1[C:2]([OH:1])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:40]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCNC(C(O)(c2ccccc2)c2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)C(C(O)(c2ccccc2)c2ccccc2)C1
Reaction time: 4 h
Yield: 44.9 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[hydroxy(diphenyl)methyl]-1-piperazine carboxylate (0.50 g, 1.4 mmol) in tetrahydrofuran (5 mL) were sequentially added diisopropylethylamine (2 mL) and chloroacetyl chloride (0.46 g, 4.1 mmol) with ice cooling, and the mixture was stirred for 4 hours while elevating the temperature to room temperature. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (0.28 g, yield 46%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC(=O)CCCC#CCBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCC#CCN1C(=O)c2ccccc2C1=O
Yield: 44.1 %

Procedure:
A mixture or potassium phthalimide (2.31 g) and methyl 7-bromohept-5-ynoate (3.0 g) in dimethylformamide (35 ml) was heated at 110° C. for 4.5 hours. The cooled solution was poured into water (75 ml) and the pH of the solution was adjusted to 6. The resulting solution was extracted with ether (4×200 ml) and the combined ether extracts were dried over magnesium sulphate, the solvent was removed and the residue was chromatographed on silica gel eluted with chloroform to give the title compound (1.56 g) m.p. 62°-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[NH:52][C:53](=[O:61])[C:54]2[CH2:60][O:59][CH2:58][CH2:57][C:55]=2[N:56]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]([NH:49][CH2:50][C:51]3[NH:52][C:53](=[O:61])[C:54]4[CH2:60][O:59][CH2:58][CH2:57][C:55]=4[N:56]=3)=[O:17])[CH2:12][CH2:13]2)=[O:7])=[CH:18][CH:19]=1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCC(C(=O)c2ccc(Cl)cc2)CC1)NCc1nc2c(c(=O)[nH]1)COCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 23.3 %

Procedure:
A solution of [4-(4-chloro-benzoyl)-piperidin-1-yl]-acetic acid (0.1 g, 0.36 mmol), EDCl (0.08 g, 0.43 mmol), HOBT (0.06 g, 0.43 mmol) and triethylamine (0.14 g, 1.4 mmol) in 20 mL of DMF, was stirred at ambient temperature for 20 min. then added 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.08 g, 0.43 mmol). The reaction mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with 50 mL of water, extracted with DCM (20 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide crude product. Purification by flash chromatography gave the title compound (37.2 mg, 0.084 mmol, 24% yield) as a white solid. MS (ESI) m/z 445.2 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.12 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61-1.83 (m, 6H), 2.21-2.30 (m, 1H), 2.50 (br. s., 2H), 2.94 (br. s., 1H), 2.99 (s, 2H), 3.32 (s, 2H), 3.35-3.46, (m, 1H), 3.83 (t, J=5.31 Hz, 1H), 4.19 (d, J=6.06 Hz, 1H), 4.34 (s, 2H), 7.60 (d, J=8.59 Hz, 2H), 8.00 (d, J=8.59 Hz, 2H), 8.20 (s, 1H) 12.40 (s, 1H). HRMS calculated for C22H26ClN4O4: 445.1643 (M+H). found (ESI, [M+H]+): 445.1658.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7](O)=[C:6]([NH2:11])[CH:5]=1)([O-])=O.[C:12]1([N:18]2[C:22](=[O:23])[CH:21]=[C:20]([CH2:24]S(O)(=O)=O)[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH2:29]>[Cr]>[NH2:11][C:6]1[CH:5]=[CH:4][CH:9]=[CH:8][C:7]=1[C:22]([OH:23])=[O:29].[C:12]1([N:18]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: O
Reactant: O=c1cc(CS(=O)(=O)O)[nH]n1-c1ccccc1
Agent: [Cr]
Product: Cc1cc(=O)n(-c2ccccc2)[nH]1
Product: Nc1ccccc1C(=O)O

Procedure:
44.0 Parts of the 1:1 chromium complex (obtained by the known process and containing 1 atom of chromium for each molecule of monoazo dyestuff) of the azo dyestuff from diazotised 4-nitro-2-amino-1-hydroxybenzene and 1-phenyl-3-sulphomethyl-5-pyrazolone are stirred in 1000 parts of hot water together with 32.2 parts of the monoazo dyestuff obtained by the known process from diazotised 1-aminobenzene-2-carboxylic acid and 1-phenyl-3-methyl-5-pyrazolone. The suspension is adjusted to pH 7 to 8 by addition of 20 parts by volume of concentrated sodium hydroxide solution and subsequently stirred at 90°-95° C. until both starting dyestuffs can no longer be detected. The unitary chromium mixed complex present in clear solution is precipitated by the addition of sodium chloride, isolated by filtration, washed with sodium chloride solution, and then dried in vacuo. After it has been ground, the dyestuff is in the form of a red, readily water-soluble powder and from a bath containing ammonium sulphate dyes wool or polyamide fibres in full yellowish orange with good fastness properties. It has the following constitution: ##STR13##
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[N:30]1([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: c1c[nH]cn1
Product: CS(=O)(=O)c1ccc(-n2ccnc2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example 199 from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK) and imidazole (20%, light grey solid, MS (m/e): 479.2 (M+H, 100%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[C:12]2([CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[O:11][CH2:10][CH2:9]1>>[C:2]1([C:15]2([OH:18])[CH2:16][CH2:17][C:12]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:13][CH2:14]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ccccc1
Product: OC1(c2ccccc2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as a white solid from 1-bromo-benzene and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.ClCC[I:45]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:45])[N:8]2[CH2:11][CH2:12][C:13]([CH3:16])([OH:15])[CH3:14])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: CC(C)(O)CCn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: ClCCI
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)CCn1c(I)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
A solution of 4-(2-chloro-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol (360 mg, 1.1 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.25 mL, 1.7 mmol) in THF (8.1 mL) was cooled to −42° C. and treated with a solution of 2.5M n-butyllithium in hexane (BuLi, 2.0 mL, 5.0 mmol) dropwise over 5 minutes. After 30 minutes at −42° C., 1-chloro-2-iodoethane (0.51 mL, 5.4 mmol) was added and the reaction mixture was slowly warmed to 0° C. over 1 hr. The mixture was quenched with a saturated solution of NH4Cl, and diluted with ethyl acetate. The aqueous layer was extracted into ethyl acetate (3×), and the combined organics were dried over sodium sulfate, filtered, and absorbed onto celite for purification by flash chromatography to afford 4-(2-chloro-8-iodo-6-morpholino-9H-purin-9-yl)-2-methylbutan-2-ol as a white foam (390 mg, 78%). LC/MS (ESI+): m/z 452 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:34]=[CH:33][C:19]([O:20][C:21]2[C:26]3=[N:27][CH:28]=[C:29]([NH:31][CH3:32])[N:30]=[C:25]3[N:24]=[CH:23][CH:22]=2)=[CH:18][C:17]=1[F:35]>>[F:35][C:17]1[CH:18]=[C:19]([O:20][C:21]2[C:26]3=[N:27][CH:28]=[C:29]([NH:31][CH3:32])[N:30]=[C:25]3[N:24]=[CH:23][CH:22]=2)[CH:33]=[CH:34][C:16]=1[NH:15][C:13]([NH:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:14]
Reactant: CNc1cnc2c(Oc3ccc(N)c(F)c3)ccnc2n1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CNc1cnc2c(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)ccnc2n1

Procedure:
Method F2 was used with 2-fluoro-5-(trifluoromethyl)phenyl isocyanate and 8-(4-amino-3-fluorophenoxy)-N-methylpyrido[3,2-b]pyrazin-3-amine to give the title compound as a white solid. Yield: 56 mg (80%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:16]O>>[CH3:16][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([CH2:6][Cl:5])[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1cccc(CCl)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
650 μl (8.8 mmol) of thionyl chloride was added dropwise to a stirred solution of 1 g (5.8 mmol) of 3-(chloromethyl)benzoic acid in 40 ml of methanol at 0° C. under a nitrogen atmosphere, then stirred at room temperature overnight. The solvent was evaporated, the residue dissolved in dichloromethane (30 ml), washed with saturated aqueous sodium bicarbonate (2×40 ml), brine (40 ml), dried over magnesium sulfate, filtered and evaporated to give 0.94 g (88%) of methyl-3-(chloromethyl)benzoate as a colorless mobile liquid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:16][CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[C:19]([O:21]C)=O)(=[O:4])=[O:3].C1(OC2C=CC=CC=2)C=CC=CC=1>>[O:21]=[C:19]1[N:10]2[CH:11]=[N:12][C:13]3[CH:14]=[CH:15][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[C:9]2=[N:16][CH:17]=[C:18]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(=CNc1ncnc2ccc(NS(C)(=O)=O)cc12)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
A mixture of dimethyl [{6-methanesulfonamido-4-quinazolinylamino)methylene]propanedioate (7.2 g) and diphenyl ether (43 ml) was stirred at 250° C. for 15 minutes and then cooled to ambient temperature to give crystals, which were filtered off and washed with a mixture of chloroform and methanol to give crystalline methyl 4-oxo-10-methanesulfonamido-4H-pyrimido[1,2-c]quinazoline-3-carboxylate (4.72 g).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1>C(O)C>[C:2]([NH:3][C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)=[S:14])#[N:1]
Reactant: N#CN
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
The suspension of monosodium cyanamide (1.9 g, 29.4 mmol) in absolute ethanol (50 mL) was slowly treated with 4-chlorophenylisothiocyanate (5.0 g, 29.4 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (5.4 g), m.p. >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=O)[CH2:10][CH2:9][S:8](=[O:15])(=[O:14])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.COC1C=CC([SH:32]2(=S)PP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=[S:32])[CH2:10][CH2:9][S:8](=[O:15])(=[O:14])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=C1CCS(=O)(=O)C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: COc1ccc(P2(=S)P[SH](=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=S1(=O)CCC(=S)Nc2ccc(Cl)cc2C1c1ccccc1F
Temperature: 25 °C

Procedure:
A solution of 13.4 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine 5,5-dioxide in 380 ml of hexamethylphosphoric acid triamide is treated with 7.7 g of 2,4-bis-(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane-2,4-disulphide, the mixture is heated to 100° for 2 hours, again cooled to room temperature and then poured into 8.3 l of water. The mixture is extracted twice with ethyl acetate and the organic extracts are washed with water and with saturated sodium chloride solution. The ethyl acetate solutions are evaporated and the residue is chromatographed on 500 g of silica gel. By elution with chloroform which contains 0.5% ethanol and crystallization from ether there is obtained 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-thiono-2H-5,1-benzothiazocine 5,5-dioxide of melting point 226°.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:16])[O:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[O:9]1>>[C:1]1(=[C:11]2[C:12](=[O:14])[O:13][C:8]([CH3:16])([CH3:7])[O:9][C:10]2=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CC1(C)OC(=O)C(=C2CCCC2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from cyclopentanone and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[C:27]([O:31][C:32]([C:34]1[N:39]2[C:40](=[O:43])[C@@H:41]([NH2:42])[C@H:38]2[S:37][CH2:36][C:35]=1[CH2:44][O:45][C:46](=[O:48])[CH3:47])=[O:33])([CH3:30])([CH3:29])[CH3:28].P([O-])([O-])(O)=O.[K+].[K+]>C(Cl)Cl.CN1CCOCC1>[C:27]([O:31][C:32]([C:34]1[N:39]2[C:40](=[O:43])[C@@H:41]([NH:42][C:16](=[O:18])[CH2:15][C:13]3[S:14][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:11][CH:12]=3)[C@H:38]2[S:37][CH2:36][C:35]=1[CH2:44][O:45][C:46](=[O:48])[CH3:47])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CC(=O)O)s1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)Cc3ccc(CNC(=O)OC(C)(C)C)s3)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The starting material can be prepared as follows: 8.15 g of 2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetic acid are dissolved in 500 ml of methylene chloride containing 3.06 ml of N-methylmorpholine, the solution, from which moisture is kept excluded, is cooled to -20° C. and 4.13 ml of chloroformic acid isobutyl ester are added dropwise whilst keeping the temperature at between -15° C. and -20° C. After 30 minutes, a solution of 9.85 g of 3-acetoxymethyl-7β-amino-3-cephem-4-carboxylic acid tert.-butyl ester in 50 ml of methylene chloride is added, after which the solution is stirred for a further 15 hours whilst slowly raising the temperature to 20° C. to 25° C. The mixture is poured out into ice-cold water, neutralised with dipotassium hydrogen phosphate and extracted repeatedly with methylene chloride. The organic extracts are washed with an aqueous saturated sodium chloride solution and dried over magnesium sulphate, after which the solvent is removed under reduced pressure. The residue is recrystallised from diethyl ether and gives 3-acetoxymethyl-7β-[2-(5-tert.-butoxycarbonylaminomethyl-2-thienyl)-acetylamino]-3-cephem-4-carboxylic acid tert.-butyl ester, melting point 76°-78° C., thin layer chromatogram (silica gel): Rf=0.44 (system: chloroform/ethyl acetate/acetic acid, 80:19:1).