Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1.Br[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=3)=[CH:18][CH:19]=2)[CH2:12][CH3:13])[CH2:6][CH2:5]1
Reactant: Cn1ccc(Br)cc1=O
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CC[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 59 Step 2. LC-MS Method 2 tR=1.203 min, m/z=971.4; 1H NMR (CDCl3) 0.97 (t, 3H), 1.12 (s, 3H), 1.19 (s, 3H), 1.79-2.02 (m, 2H), 2.11-2.24 (m, 4H), 2.29-2.42 (m, 1H), 2.81 (m, 1H), 3.50 (s, 3H), 5.40 (m, 1H), 6.28 (d, 1H), 6.64 (s, 1H), 7.02 (d, 2H), 7.18 (m, 3H), 7.20 (m, 2H), 7.28 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=O)=[C:4]([Cl:11])[N:3]=1.C(O)(=O)C.Cl.[NH2:17][OH:18]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[N:17][OH:18])=[C:4]([Cl:11])[N:3]=1
Reactant: NO
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(C=NO)c(Cl)n1
Yield: 84.1 %

Procedure:
Following the method of Bell et al. (J. Heterocyclic Chem. 1983, 20, 41), to a solution of 29.6 g (154 mmol) 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde in 31 acetic acid in a 2-necked flask at room temperature was added dropwise with stirring a solution of 11.8 g (170 mmol) hydroxylamine hydrochloride in 2.31 ethanol. Stirring was continued for 3 h at room temperature during which time crystallisation occurred. The crystals were collected by filtration to afford 26.8 g (84%) 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde oxime as a light yellow crystalline solid. ES-MS m/e (%): 209 ([M{37Cl, 37Cl}-H]−, 20), 207 ([M{37Cl, 35Cl}-H]−, 55), 205 ([M{35Cl, 35Cl}-H]−, 100).
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12]([N:14]1[CH2:20][C:16]2([NH:19][CH2:18][CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][N:30]=[C:31]=[O:32].C(N(CC)CC)C>C(#N)C>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH:30][C:31]([N:19]1[C:16]2([CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:20]2)[CH2:17][CH2:18]1)=[O:32]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2(CCN2)C1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2(CCN2C(=O)NCc2ccc(Cl)cc2Cl)C1
Reaction time: 8 h
Yield: 131.3 %

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-1,6-diaza-spiro[3.3]heptane oxalate (350 mg, 719 μmol) in acetonitrile (5 mL) was added 2,4-dichloro-1-(isocyanatomethyl)benzene (291 mg, 1.44 mmol) followed by triethylamine (201 μl, 1.44 mmol) and the mixture was stirred overnight. Further 2,4-dichloro-1-(isocyanatomethyl)benzene (100 mg, 0.49 mmol) was added. After 1 hour at ambient temperature, the reaction was concentrated under reduced pressure. The residue was purified by chromatography (SiO2; heptane:ethyl acetate 1:4) to give the title compound (378 mg, 65%) as a colorless foam. MS (EI) m/e: 400.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[N:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1>>[Cl:35][C:32]1[CH:31]=[N:30][C:29]([N:23]2[CH2:22][CH2:21][C:20]3([CH2:19][C:18]4([O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:27]4)[CH2:26]3)[CH2:25][CH2:24]2)=[N:34][CH:33]=1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: Clc1cnc(Cl)nc1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4ncc(Cl)cn4)CC3)C2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2,5-dichloro-pyrimidine following a procedure analogous to that described for Example 4. LC (method 1): tR=1.17 min; Mass spectrum (ESI+): m/z=502/504 (Cl) [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18](=O)/[CH:19]=[CH:20]/[N:21](C)C)=[N:12]3)=[CH:10][C:4]=2[O:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34]N>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH:16]=[CH:15][C:14](=[O:17])[C:13]([C:18]4[N:34]([C:28]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=5[F:26])[N:21]=[CH:20][CH:19]=4)=[N:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: NNc1cc(F)ccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc3c(c2)OC(F)(F)O3)ccc1=O
Product: O=c1ccn(-c2ccc3c(c2)OC(F)(F)O3)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-11) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=431.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:5]([NH:7][CH:8]([C:14](=[O:16])[CH3:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=O.OS(O)(=O)=O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:16][C:14]([CH3:15])=[C:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=2)[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: COC(=O)CC(NC(=O)c1ccc(C)c(Br)c1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)Cc1nc(-c2ccc(C)c(Br)c2)oc1C
Reaction time: 1 h

Procedure:
The total crude material prepared in Example 80 was dissolved in acetic anhydride (25 mL) followed by slow addition of conc. H2SO4 (1 mL). The pot temperature reached 90° C. The reaction was then held at 90° C. for 1 h, cooled, and the acetic anhydride removed in vacuo. The residue was poured into ice water (250 mL) and extracted with EtOAc (300 mL total). The organic layer was then extracted with 1 N HCl (100 mL), saturated NaHCO3 (100 mL) and brine, separated, then dried with NaSO4 and concentrated to afford the title ester (4.6 g). The crude product used in the next step (Example 82).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:32][C:33]1[N:38]=[C:37]([NH:39][CH2:40][CH2:41][NH:42][C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50](=O)[CH2:51][N:52]([CH2:54][CH2:55][OH:56])[CH3:53])=[C:45]([C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][C:59]=3[Cl:65])[CH:44]=2)[CH:36]=[CH:35][C:34]=1[N+:66]([O-:68])=[O:67]>C1COCC1>[NH2:32][C:33]1[N:38]=[C:37]([NH:39][CH2:40][CH2:41][NH:42][C:43]2[CH:48]=[CH:47][C:46]([N:49]3[CH2:50][CH2:51][N:52]([CH3:53])[CH2:54][C:55]3=[O:56])=[C:45]([C:58]3[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][C:59]=3[Cl:65])[CH:44]=2)[CH:36]=[CH:35][C:34]=1[N+:66]([O-:68])=[O:67]
Reactant: CN(CCO)CC(=O)Nc1ccc(NCCNc2ccc([N+](=O)[O-])c(N)n2)cc1-c1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NCCNc3ccc([N+](=O)[O-])c(N)n3)cc2-c2ccc(Cl)cc2Cl)C(=O)C1
Temperature: 55 °C

Procedure:
DEAD (2.5 eq) and PPh3 (2 eq) were added to N-[4-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-2-(2,4-dichlorophenyl)phenyl]-2-[(2-hydroxyethyl)-methylamino]acetamide (1 eq) dissolved in THF at room temperature. The reaction was heated to 55° C. for 1 hour until completion was determined by LC/MS. The reaction was concentrated and purified by silica column chromatography, eluting with MeOH in CH2Cl2 (5:95, v/v). After collecting the purified fractions and concentrating, 1-[5-({2-[(6-amino-5-nitropyridin-2-yl)amino]ethyl}amino)-2′,4′-dichloro-1,1′-biphenyl-2-yl]-4-methylpiperazin-2-one was attained as a light yellow glass (LC/MS m/z 531.4 MH+) in quantitative yields.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:6]1[CH:19]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][C:5]2=1.[Li+].[OH-].C(OCC)(=O)C.Cl>C(O)C.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:6]1[CH:19]([CH2:24][C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][C:5]2=1
Reactant: CCOC(=O)CC1CCCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(F)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CC1CCCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(F)cc21
Temperature: 25 °C

Procedure:
To 230 mg of the ester from Step 1 in 3.0 mL of ethanol was added 2.2 mL of 0.5M aqueous LiOH and the resultant mixture heated at reflux for 8 h. The reaction mixture was then cooled to room temperature, poured into ethyl acetate and acidified with concentrated HCl. The organic layer was separated, washed with 1N HCl and brine (2x) and dried over MgSO4. Concentration gave a yellow oil which solidified on standing. Trituration with hexane gave the title compound. IR (KBr) 1710 cm-1. 'H NMR (CDCl3, 250 MHz) w 1.35-1.70 (m, 2H), 1.80-2.12 (m, 4H), 2.50-2.65 (m, H), 2.54 (d,d, J=6.5, 16.0 Hz, 1H), 2.72 (d,d, J=8.5 Hz, 1H), 2.95-3.06 (m, 1H), 3.46-3.58 (m, 1H), 5.28 (d, J=7.5 Hz, 1H), 5.43 (d, J=7.5 Hz, 1H), 6.80-6.92 (m, 1H), 6.83 (d, J=8.0 Hz, 2H), 7.26 (d,d, J=4.0, 9.0 Hz, 1H), 7.16 (d,d, J=2.5, 10.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H).
Reaction SMILES: [ClH:1].[C:2]1([S:8]([CH2:11][C:12]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([O:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)[C:15]([C:32]3[CH:36]=[CH:35][O:34][CH:33]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[NH2:24][CH2:23][CH2:22][O:21][C:16]1[C:15]([C:32]2[CH:36]=[CH:35][O:34][CH:33]=2)=[CH:14][CH:13]=[C:12]([CH2:11][S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])[C:17]=1[C:18]([OH:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: NCCOc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
Hydrogen chloride (4M in dioxane, 2 ml) was added to a solution of 6-(benzenesulphonylmethyl)-2-[2-(t-butoxycarbonyl)aminoethoxy]-3-(furan-3-yl)benzoic acid (Intermediate 6, 0.018 g) in dioxane (0.5 ml) and the resultant mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness and the residue was triturated with ether. The solid was collected by filtration then purified by chromatography on silica, eluting with a mixture of DCM, methanol, acetic acid and water in a ratio of 240:20:3:2 changing to 120:15:3:2. After evaporation of the solvent, the residue was treated with hydrochloric acid (1M) and evaporated to dryness to give 2-(2-aminoethoxy)-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoic acid hydrochloride (0.008 g) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][NH2:30])[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: NCCCc1cccnc1
Reactant: CCCc1c(OCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCC(=O)NCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid was allowed to react with 3-pyridine propanamine according to procedure A and the product was purified by chromatography on silica gel to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[3-(3-pyridinyl)propyl]butanamide, the title compound, mp 97°-98° (from methylene chloride-ether) in 88% yield.
Reaction SMILES: O[CH:2]([C:9]1[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=1)[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1>ClCCl.S(Cl)(Cl)=O>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][C:9]2[CH:10]=[C:11]([C:20]([CH3:24])([CH3:23])[C:21]#[N:22])[CH:12]=[C:13]([C:15]([CH3:19])([CH3:18])[C:16]#[N:17])[CH:14]=2)[CH:4]=1
Reactant: CC(C)(C#N)c1cc(C(O)c2cccnc2)cc(C(C)(C)C#N)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)(C#N)c1cc(Cc2cccnc2)cc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Example 34 (50 mg) in dichloromethane (2 ml) and thionyl chloride (0.1 ml) was heated under reflux for 1 h, then evaporated to dryness under reduced pressure. The residue was dissolved in ethanol, 10% palladium-on-carbon catalyst was added, and the mixture was shaken in an atomosphere of hydrogen at room temperature and atmospheric pressure for 1 h. The mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the residue was partitioned between aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl acetate phase was separated, dried and evaporated to dryness under reduced pressure, and the residue was purified by flash column chromatography, eluting with ethyl acetate, to give 2,2'-[5-(3-pyridylmethyl)-1,3 -phenylene]di(2-methylpropiononitrile), mp 82°-84°.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:11]=[CH:10][NH:9][C:8]=2[CH2:12][OH:13])=[CH:4][CH:3]=1.[CH2:16]([O:20][CH:21]1[CH:23]([C:24](O)=[O:25])[C:22]1([CH3:28])[CH3:27])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][CH:21]1[CH:23]([C:24]([O:13][CH2:12][C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[O:25])[C:22]1([CH3:28])[CH3:27])[CH:17]([CH3:19])[CH3:18]
Reactant: OCc1[nH]ccc1Cc1ccc(Cl)cc1
Reactant: CC(C)COC1C(C(=O)O)C1(C)C
Product: CC(C)COC1C(C(=O)OCc2[nH]ccc2Cc2ccc(Cl)cc2)C1(C)C

Procedure:
Using the above procedure, 3-(4-chlorobenzyl)-pyrrolylmethyl alcohol is reacted with 3-(i-butoxy)-2,2-dimethylcyclopropanecarboxylic acid to yield 3-(4-chlorobenzyl)-pyrrolylmethyl 3-(i-butoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:11])[N:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.ClCCl.[CH2:15](Br)[C:16]#[CH:17]>CO>[CH3:8][N:6]1[CH:7]=[C:2]([NH:1][CH2:17][C:16]#[CH:15])[C:3](=[O:11])[N:4]([CH3:10])[C:5]1=[O:9]
Reactant: Cn1cc(N)c(=O)n(C)c1=O
Reactant: C#CCBr
Solvent: ClCCl
Solvent: CO
Product: C#CCNc1cn(C)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of Step 1 intermediate (1.4 g, 9.023 mmol) in 1:1 mixture of dichloromethane and methanol (28 mL) was added propargyl bromide (1.4 mL) and the mixture was stirred at room temperature for 2 h. Reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to give 500 mg of the product.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(C(F)(F)F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-(trifluoromethyl)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[C:12]([N+:16]([O-:18])=[O:17])=[C:11](Cl)[C:10]=2Cl)=[CH:4][N:3]=1.NC1N=C(N)C([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=CN=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=2[Cl:36])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2cc(Cl)c([N+](=O)[O-])c(Cl)c2Cl)c(N)n1
Reactant: Nc1ncc(-c2cccc(Cl)c2Cl)c(N)n1
Product: Nc1ncc(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
This compound was made in an analogous manner to the compound of Example 5 from 2,4-diamino-5-(2,3-dichlorophenyl)pyrimidine (Example 21). The reaction gave a mixture of the 4-nitro and 5-nitro derivatives from which the title compound was separated by column chromatography (SiO2, EtOAc), mp. 237°-9° C. Also separated in this manner was 2,4-diamino-5-(2,3-dichloro-5-nitrophenyl)pyrimidine, mp. 264°-6° C.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([CH3:12])[N:11]=1.NC(N)=O.[N+:17]([O-])([OH:19])=[O:18]>>[CH3:6][C:7]1[NH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH3:12])[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1c[nH]c(C)n1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Product: Cc1nc(C)c([N+](=O)[O-])[nH]1
Temperature: 200 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
Sulfuric acid (30 ml, 0.56 mole) was added dropwise to 2,4-dimethylimidazole (10 g, 0.104 mole), and urea (6.24 g, 0.104 mole), in a 1 l. flask cooled in ice. This was followed by the addition of fuming nitric acid (30 ml, 0.72 mole). When all had been added, the flask was heated at 200° C. for 1-2 minutes, whereupon a vigorous reaction ensued, necessitating the removal of the heat. When the reaction subsided, heating is continued for 10 minutes. The flask was then allowed to cool, and the reaction mixture was added to 300 ml of H2O. The solution was adjusted to pH 5 with aqueous sodium hydroxide (about 40 g of sodium hydroxide was required). The resulting precipitate was filtered off and dried in vacuum to give 9.9 g of 2,4-dimethyl-5-nitroimidazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[C:43]([CH3:45])[N:42]=[C:41]([CH3:46])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[C:41]([CH3:46])[N:42]=[C:43]([CH3:45])[CH:44]=2)[CH:34]=1)=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J35) (251 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (172 mg, 49%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH3:13])[C:10]=2[N:11]=1.[Cl:14][C:15]1[C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Cl:14][C:15]1[C:20]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:12][CH3:13])[C:10]=3[N:11]=2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: COc1ncnc2ccc(Cl)nc12
Reactant: CC1(C)OB(c2cccnc2Cl)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncnc2ccc(-c3cccnc3Cl)nc12
Temperature: 98 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A reaction flask was charged 6-chloro-4-methoxypyrido[3,2-d]pyrimidine (3.5 g, 17.8 mmol), 2-chloro-3-pyridineboronic acid pinacol ester (4.35 g, 18.2 mmol), Na2CO3 (4.0 g, 38.2 mmol) and 1,4-dioxane (100 mL) and a stir bar. The contents were degassed by vacuum and back filled with argon three times while stirring. Subsequently, Pd(PPh3)3 (0.87 g, 0.75 mmol) was added to the reaction contents, repeated degassing cycles and heated under argon at 98° C. The heating was stopped after overnight, the yellow hot heterogeneous reaction mixture was suction filtered on a Buchner funnel and washed the cake with additional amount of dioxane (30 mL). The pale yellow clear filtrate solution was passed through a pad of Celite® and concentrated the filtrate. The crude pale yellow solid residue was partitioned between CH2Cl2 (150 mL)/water (50 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The crude concentrate was stirred in EtOAc (30 mL) and suction filtered. The filter cake was washed further with EtOAc (10 mL) and dried to obtain 1.6 g of 6-(2-chloropyridin-3-yl)-4-methoxypyrido[3,2-d]pyrimidine (purity: 95%) as a white solid. The filtrate was concentrated and purified the concentrate by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g, 0-30-60% EtOAC/hexanes eluting solvent gradient) to obtain additional 0.65 g of titled compound. 1H NMR (300 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.57 (dd, J=4.8, 2.0 Hz, 1H), 8.45 (d, J=8.7 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.13 (dd, J=7.6, 2.0 Hz, 1H), 7.63 (dd, J=7.6, 4.8 Hz, 1H), 4.16 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@H:50]([C:52]([F:55])([F:54])[F:53])[CH2:51][N:43]2[C:42]1=[O:56]>>[CH2:33]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@H:50]([C:52]([F:53])([F:55])[F:54])[CH2:51][N:43]2[C:42]1=[O:56])=[O:10])[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-2-oxo-1-o-tolylazepan-3-yl)-N6-((4S,8S,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (8.2 mg, 0.016 mmol) and Intermediate 60 (3.5 mg, 0.013 mmol) to give a white solid (5.9 mg, 58% yield). Anal. Calcd. for C43H51F3N4O4S m/z 776.7. found: 777.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.42-6.89 (m, 14H), 5.86 (s, 2H), 5.11 (dd, J=14.2, 7.0 Hz, 1H), 4.81 (dd, J=10.6, 6.6 Hz, 2H), 4.38-4.26 (m, 1H), 4.09-3.86 (m, 2H), 3.54 (d, J=16.2 Hz, 1H), 3.40-3.09 (m, 3H), 2.91-2.38 (m, 7H), 2.21 and 2.14 (s, 3H), 2.28-2.07 (m, 1H), 2.07-1.77 (m, 5H), 1.75-1.22 (m, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[C:9]1([CH2:15][CH2:16][CH2:17][Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([OH:8])[CH2:17][CH2:16][CH2:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1sccc1Br
Product: OC(CCCc1ccccc1)c1sccc1Br

Procedure:
Prepared according to the procedure described in Example 5, Step 1, using the following starting materials: 3-bromo-thiophene-2-carbaldehyde and 3-phenyl-propyl magnesium bromide.