Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:21][C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:32][C:31]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[O:30][C:29]2=[O:45])=[CH:24][CH:23]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:21][C:22]4[N:27]=[CH:26][C:25]([N:28]5[CH2:32][C:31]6([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]6)[O:30][C:29]5=[O:45])=[CH:24][CH:23]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11](=[O:12])[N:13]([CH3:15])[CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ccc(N)nc1)C(=O)O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5(CCN(C(=O)OC(C)(C)C)CC5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 62.5 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (133 mg, 0.45 mmole) was combined with tert-butyl 3-(6-aminopyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (158 mg. 0.45 mmole) which gave tert-butyl 3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) pyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (170 mg) in 62% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.89 (s, 1H), 8.76 (s, 1H), 8.46 (d, J=9.03 Hz, 1H), 8.38 (d, J=2.51 Hz, 1H), 7.97-7.92 (m, 1H), 6.40 (s, 1H), 4.78-4.68 (m, 1H), 3.83-3.73 (m, 2H), 3.71 (s, 2H), 3.33-3.21 (m, 2H), 3.02 (s, 6H), 2.54-2.40 (m, 2H), 2.05-1.86 (m, 6H), 1.78-1.58 (m, 4H), 1.38 (s, 9H) HR-MS m/z 605.3221 (M+H)+
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14](C2CCCCC2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH2:41][CH2:42][CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[C:32]1([CH2:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@H:14]([CH:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:47][CH2:48]2)[C:31]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc2cc(CCC3CCNCC3)ccc2c1
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(CCc3cccc4ccccc34)CC2)[C@@H](c2ccccc2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step I) and 4-(2-napthylethyl)piperidine (from EXAMPLE 162, Step C) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: 1H NMR (500 MHz, CD3OD) a 1.103.80 (m, 33H), 7.10-7.60 (m, 9H), 7.68 (d, J=7.7, 1H), 7.83 (d, J=8.0, 1H), 7.99 (d, J=8.5, 1H); ESI-MS 539 (M+H); HPLC A: 2.83 min.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:12]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)([CH3:14])[CH3:13]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH:12]([CH3:14])[CH3:13])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(C)Oc1ccccc1B(O)O
Product: CC(C)Oc1ccccc1-c1cccn2nc(Cl)nc12

Procedure:
2-Chloro-8-(2-isopropoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine and 2-isopropoxyphenylboronic acid in a manner analogous to Example 2c (0.24 g, 40%). MS=288 (MH)+.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][C@@H:15]([CH2:25][OH:26])[O:14][CH2:13]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[C:29]=1F>CN(C=O)C>[Si:3]([O:10][CH2:11][C@H:12]1[N:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][C@@H:15]([CH2:25][O:26][C:29]2[C:30]([N+:34]([O-:36])=[O:35])=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])[O:14][CH2:13]1)([C:6]([CH3:9])([CH3:7])[CH3:8])([CH3:5])[CH3:4]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](COc2c(F)cccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a stirring solution of sodium hydride (0.257 g, 6.43 mmol) (pre-washed in hexanes) in DMF (15.30 mL) at 0° C., tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-(hydroxymethyl)morpholine-4-carboxylate (Example 1, Step 5) (1.66 g, 4.59 mmol) in DMF (2 mL) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour. At this point, 1,2-difluoro-3-nitrobenzene (0.494 mL, 4.50 mmol) in 0.5 mL of DMF was added dropwise and the final solution was slowly warmed toward room temperature and stirred for 1 hour. Complete by LC/MS at this time. The contents were quenched by adding saturated aqueous sodium bicarbonate and then extracted between water and EtOAc (3×75 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification on silica gel (120 g) eluting with a gradient of 0-60% EtOAc/hexanes afforded the title compound (1.68 g, 3.36 mmol, 73% yield) as a yellow oil, MS (ESI): m/z=401.11 (M+H-boc).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.C(OC(=O)C)(=O)C.[CH:20](=O)[C:21]1[CH:28]=[CH:27][CH:26]=[C:23]([CH:24]=[O:25])[CH:22]=1>C1(C)C(C)=CC=CC=1>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2](/[CH:1]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Reactant: O=Cc1cccc(C=O)c1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Yield: 52 %

Procedure:
Starting with 6.56 g of 2-methyl-7-chloroquinoline, 10.4 ml of acetic anhydride and 4.95 g of isophthalaldehyde in 100 ml of xylene and using the procedure of Preparation Il, there was obtained 5.64 g of the desired product as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:11])/[CH:2]=[C:3](\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])/[CH3:4].[Cl-].[CH3:13][O:14][C:15](=[O:19])[C:16](O)=[O:17]>>[CH3:13][O:14][C:15](=[O:19])[C:16]([NH:11][CH2:1]/[CH:2]=[C:3](/[CH3:4])\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:17]
Reactant: COC(=O)C(=O)O
Reactant: CC(C)=CCC/C(C)=C\CN
Agent: [Cl-]
Product: COC(=O)C(=O)NC/C=C(/C)CCC=C(C)C

Procedure:
Said substance is manufactured according to AAV 1, by converting nerylamine and oxalic acid monomethylester chloride with each other and the product is purified by column chromatography (pentane/diethyl ether=3/2).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Nc1cncc(Cl)c1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cncc(Cl)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 3-Amino-5-chloropyridine instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=343.0, 345.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:32]([N:34]([C:41](=[O:44])[CH:42]=[CH2:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH:43]=[CH:42][C:41](=[O:44])[N:34]([CH2:32][CH3:33])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CC(=O)N(CC)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Product: CCN(C(=O)C=Cc1cc(C)c(N(Cc2cccnc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1)c1ccccc1
Yield: 65.4 %

Procedure:
In the same manner as described in Example 203, 550.4 mg (1.0 mmol) of the product of Example 89 and 425 mg (2.43 mniol) of N-ethylacryianilide provided 392 mg (65%) of the desired product as a brown solid. Electrospray Mass Spec 600(M+H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[NH2:8][C:9]1[C:18]([F:19])=[C:17](F)[C:16]([O:21][CH:22]([F:24])[F:23])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:28]([OH:30])=[O:29])=[CH:13][N:14]2[CH:25]1[CH2:27][CH2:26]1>N1C=CC=CC=1>[NH2:8][C:9]1[C:18]([F:19])=[C:17]([N:6]2[CH2:5][CH2:4][NH:3][CH:2]([CH3:1])[CH2:7]2)[C:16]([O:21][CH:22]([F:23])[F:24])=[C:15]2[C:10]=1[C:11](=[O:31])[C:12]([C:28]([OH:30])=[O:29])=[CH:13][N:14]2[CH:25]1[CH2:26][CH2:27]1
Reactant: Nc1c(F)c(F)c(OC(F)F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2OC(F)F)CCN1
Reaction time: 2 h
Yield: 64.9 %

Procedure:
1.30 g (0.013 moles) of 2-methylpiperazine was added to a solution of 0.90 g (0.0026 moles) of 5-amino-1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (prepared as described in Preparation 11) in 8 ml of pyridine, and the mixture was stirred at 105°-110° C. for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and the resulting mixture was neutralized (to about pH 7) by the addition of acetic acid; the mixture was then extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was washed with ethanol to give 0.72 g of 5-amino-1-cyclopropyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a yellow powder, melting at 283°-286° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(CCCl)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Cl)CC1
Yield: 66.5 %

Procedure:
A mixture of 2-chloro-5-nitrobenzenamine (7.95 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (8.86 g) in chlorobenzene (40 ml) under nitrogen was heated to reflux for 3 days before cooling and diluting with dichloromethane (60 ml). The reaction mixture was then extracted with water (2×500 ml), the aqueous layers combined and basified with 2N sodium hydroxide, then extracted with dichloromethane (4×400 ml). The combined, dried extracts were concentrated in vacuo to give a dark brown oil (7.82 g) which was purified by FCC eluting with ether to give a dark brown oil which crystallised upon standing. This material was dissolved in ethanol (40 ml) and boiled up with some charcoal (300 mg). The hot ethanolic suspension was filtered through a pad of hyflo and concentrated in vacuo to give the title compound as a yellow oil which crystallised on standing (5.25 g) m.p.63°-64° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10]CC)=[O:9])[CH:4]=1.[OH-].[Li+].Cl>C1COCC1.O>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1
Reactant: CCOC(=O)c1cc(CBr)on1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
Ethyl 5-(bromomethyl)isoxazole-3-carboxylate (4.27 mmol, 1 g) and lithium hydroxide (10.68 mmol, 0.256 g) were dissolved in THF (6.5 ml) and water (6.5 ml). The resulting mixture was stirred for 30 min at RT. The pH was adjusted to 4 with 1 M HCl and diluted with water. The mixture was extracted three times with EtOAc. The combined organics were dried, filtered and evaporated. 0.543 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 4.88 (s, 2H), 6.92 (s, 1H), 14.09 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[N:21]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([N:24]2[CH2:25][CH2:26][N:21]([CH2:27][CH2:28][OH:29])[CH2:22][CH2:23]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: OCCN1CCNCC1
Product: O=C(c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1)N1CCN(CCO)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 2-piperazin-1-ylethanol (26.0 mg, 0.2 mmol). The title compound was obtained as a solid (23.0 mg, 50% yield). 1H NMR (300 MHz, d6-DMSO) δ: 8.75 (2H, s), 7.80 (1H, s), 4.87 (4H, m), 4.23 (4H, m), 4.04 (2H, m), 3.22 (2H, m). MS m/z: 462.90, 464.90 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[C:26]([Cl:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-dichlorobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH: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][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N: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][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In 300 ml of chloroform, 100 g of 4-chloro-3-nitrobenzenesulfonyl chloride was dissolved, and cooled to 0° C. Thereto, a solution of 84.3 g of methyloctadecylamine in chloroform was added dropwise. Then, 39.5 g of triethylamine was added dropwise as the reaction system was kept at a temperature from 0° C. to 10° C. After the conclusion of the addition, the reaction was run for 1 hour. Then, the solvent was distilled away, and the residue was dissolved in 500 ml of methanol under heating. The solution was allowed to stand for a while in order to cool. Thereupon, crystals separated out, and they were filtered off. Yield: 109 g, Percent yield: 71.2%, Melting point: 86°-87° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=2)=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2ccc(C)cc2[nH]1
Product: Cc1ccc2cc(C(=O)O)n(Cc3cccc4ccccc34)c2c1

Procedure:
Using general procedure B, 6-methyl-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 314.1 ([M−H]−).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].CC(C)([O-])C.[K+]>CN(C)C=O>[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1F
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a microwave tube, 300 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 are introduced into 1 ml of N,N-dimethylformamide, 623 mg of 2-fluoroaniline and 378 mg of potassium tert-butoxide. 2 ml of N,N-dimethylformamide are then added. The tube is then microwave-heated at 150° C. for 20 minutes. The reaction mixture is concentrated under reduced pressure. 30 ml of water and 10 ml of ethyl acetate are added and the resulting mixture is thus stirred for 1 h 30. The precipitate formed is filtered off and rinsed with ethyl acetate, ethyl ether and then petroleum ether. The solid obtained is dried in a rotary evaporator and 93 mg of N-(2-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are thus obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:45]=[CH:44][C:27]([C:28]([NH:30][C@H:31]([C:39]([O:41]CC)=[O:40])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:29])=[CH:26][CH:25]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][C@H:31]([C:39]([OH:41])=[O:40])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])=[CH:44][CH:45]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(Cc2ccc3nc(N)nc(O)c3c2)Cc2c[nH]c(=O)[nH]c2=O)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(O)c2cc(CN(Cc3c[nH]c(=O)[nH]c3=O)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)ccc2n1
Reaction time: 1.5 h

Procedure:
Diethyl N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamate (0.327 g) was suspended in a mixture of water (7 ml) and ethanol (2 ml) and treated with 1 N NaOH aq. (6 mol. eq.) Vigorous shaking gave a solution within 30 min. After a further 1.5 hr. the solution was clarified by filtration and the pH brought to 4.0 using 1 N HCl aq. A particulate precipitate of the product resulted. It was freed from inorganic ions by three cycles of suspension-centrifugation-decantation. The amorphous white solid was dried at 40° C. in vacuo, to yield the pure diacid, N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamic acid (CB 3743), as its dihydrate (68%), m.p. 250°-255° C. The structure was confirmed by elemental analysis (C,H,N) and by uv spectroscopy (spectrum determined in 0.1 N NaOH eq.). λ(nm) (ε) maxima: 310 (29,200), 276.5 (22,000), 230 (50,700); minima: 282.5 (21,500), 251.5 (11,600).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([O:24]CC)=[O:23])[N:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:15]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([OH:24])=[O:23])[N:20]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1nnc(-c2cc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1nnc(-c2cc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl (5-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]isoxazol-5-yl}-2H-tetrazol-2-yl)acetate (1.3 g, 2.62 mmol) in THF (15 mL) and MeOH (5 mL) was added 1M sodium hydroxide (5.25 mL, 5.25 mmol). The mixture was stirred at room temperature for 1 h. Volatile solvents were removed in vacuo. The residue was diluted with water (20 mL), acidified with 1M HCl (6 mL) and extracted with EtOAc. The EtOAc extract was washed with water, dried (Na2SO4) and concentrated. The residue was triturated with diethyl ether to give the crude product, containing about 5% of the 1-isomer. Further purification by trituration in isopropyl acetate (2×, 80° C. overnight, then room temperature overnight) provided the title compound as a beige powder.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:9][N:10]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][N:19]=[C:18]([Cl:25])[N:17]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:7][CH3:8])C.Cl>C(O)C>[Cl:25][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:4](=[O:3])[CH:5]([CH2:6][CH2:7][CH3:8])[CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:16]=2[N:17]=1
Reactant: CCCC(CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1)C(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCCC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Yield: 68 %

Procedure:
To a solution of 0.384 g (0.001 mole) of (rac)-2-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-pentanoic acid ethyl ester (IV-16) in 5 mL of ethanol was added 0.562 g (0.0025 mole) of stannous chloride dihydrate and 0.1 mL of hydrochloric acid. The mixture was heated to 60 degrees for 2 hrs. The solvent was evaporated under reduced pressure. The residue was taken up in 20 mL of water and extracted with three times with 20 mL of ethyl acetate. The combined organic layers were dried with magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) gave 0.210 g of (rac)-2-chloro-9-cyclopentyl-7-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-16) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[N+:20]([C:23]1[CH:32]=[C:31]2[C:26]([CH2:27][CH2:28][CH2:29][NH:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH3:13])=[C:6]([S:8]([N:30]2[C:31]3[C:26](=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:32]=3)[CH2:27][CH2:28][CH2:29]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCC2
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 5-chloro-2-methoxybenzenesulfonyl chloride (2.75 g, 11.20 mmol) in dichloromethane (0.15 L) was treated with pyridine (14.59 mL, 181.26 mmol) and a solution of 7-nitro-1,2,3,4-tetrahydro-quinoline (1.90 g, 10.66 mmol) in dichloromethane (6.00 mL). The mixture was stirred at room temperature for 120 hours, then the volatiles were evaporated. The residue was redissolved in dichloromethane and washed with water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by flash chromatography (dichloromethane/methanol gradient) to yield 1-(5-chloro-2-methoxy-benzenesulfonyl)-7-nitro-1,2,3,4-tetrahydro-quinoline as an orange solid, 3.46 g (85%), MS (ISP): m/e=383.1 (M+H).