Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.C(O)(=O)C.C(NC=NCCCC)CCC.[H][H]>[Ni].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: CCCCN=CNCCCC
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(N)c1

Procedure:
40.8 g of 1-chloro-2,4-dinitrobenzene, 2 g of Raney nickel (60%, aqueous), 2.3 g of N,N'-dibutylformamidine acetate and 120 ml of methanol are introduced in an autoclave equipped with gas introduction stirrer. The air in the autoclave is then displaced by nitrogen and then by hydrogen. The hydrogenation is carried out at a pressure of 10 bar and a temperature of 60° C. The hydrogenation time is 11/4 hours. 1-Chloro-2,4-diaminobenzene, 97% pure (analysed as 1-Chloro-2,4-acetamidobenzene by liquid chromatography), is obtained in quantitative yield.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](I)[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([C:13]2[CH:14]=[CH:15][C:10]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: Clc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A solution of [1,1′-biphenyl]-4-ylboronic acid (8.47 g, 42.8 mmol), 1-chloro-3-iodobenzene (10 g, 41.9 mmol), Pd(PPh3)4 (0.969 g, 0.839 mmol) and K2CO3 (17.4 g, 126 mmol) in toluene (270 ml) and water (90 ml) was refluxed under nitrogen for 4.5 h. After cooling to room temperature, the organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine and water, dried over Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography on silica gel with heptane/DCM (98/2, v/v) as eluent to yield 3-chloro-1,1′:4′,1″-terphenyl (9.3 g, 84%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][C@@H:43]2[O:45][CH2:44]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][C@H:43]1[CH2:44][O:45]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (300 mg, 0.93 mmol), (prepared as described in Example 49), potassium carbonate (385 mg, 2.79 mmol) and (2R)-(−)-glycidyl tosylate (426 mg, 2.79 mmol) in DMF (15 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate exaporated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate solution. The organic layer was then dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow solid. This was triturated with ether, filtered off and dried to give (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline as a yellow solid (185 mg, 53%).
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4]COC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][C:38]=3[C:44]([F:47])([F:46])[F:45])=[N:33][CH:32]=2)=[CH:27]1.Cl.ClCCN(C)C>C(Cl)Cl.CO>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]2[S:35][C:31]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)=[CH:32][N:33]=2)=[C:38]([C:44]([F:47])([F:46])[F:45])[CH:39]=1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1
Reactant: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: CN(C)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CN(C)CCOc1ccc(Nc2ncc(-c3ccsc3)s2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-ylamino)-3-trifluoromethyl-phenol (Example 28) and using (2-chloroethyl)-dimethylamine hydrochloride. The title compound: ES-MS: 413.9 [M+H]+; single peak at tR=3.17 min (System 2); Rf=0.22 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1.[Cl:23][C:24]1[C:25]([O:27][C:28](=[O:31])[C:29]=1[Cl:30])=[O:26]>O1CCCC1>[CH:15](=[C:12]1[C:8]2=[N:9][C:10]3[CH:11]=[C:2]([NH:1][C:28](/[C:29](/[Cl:30])=[C:24](/[Cl:23])\[C:25]([OH:27])=[O:26])=[O:31])[CH:3]=[CH:4][C:5]=3[C:6](=[O:22])[N:7]2[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Solvent: C1CCOC1
Product: O=C(O)/C(Cl)=C(/Cl)C(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Reaction time: 3 h
Yield: 31.7 %

Procedure:
6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one (2 g) was reacted with 2,3-dichloro-maleic anhydride (3.46 g) in tetrahydrofuran (130 ml) under stirring at the reflux temperature for 3 hours. After cooling the solution was evaporated in vacuo to dryness: the residue was suspended in hot ethyl acetate and filtered. Crystallization from CH2Cl2 -ethyl acetate gave 1 g of (Z)-3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-2,3-dichloro-2-propenoic acid, m.p. 160°-165° C. (dec.),
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:38])([F:37])[C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][C:28]4[N:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=O)[CH:29]=4)=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl.CN(C=O)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[F:38][C:8]([F:37])([F:7])[C:9]1[CH:10]=[C:11]([NH:15][C:16]([N:18]2[C:26]3[C:21](=[CH:22][C:23]([O:27][C:28]4[CH:29]=[C:30]([C:34]([N:43]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)=[O:36])[N:31]=[CH:32][N:33]=4)=[CH:24][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc(Oc3ccc4c(c3)CCN4C(=O)Nc3cccc(C(F)(F)F)c3)ncn2)CC1
Reaction time: 1 h

Procedure:
60 μl (0.7 mMol) oxalylchloride are added to a solution of 200 mg (0.45 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid in 4 ml CH2Cl2 and 1 drop of DMF. After 1 h at rt, the solution is concentrated in vacuo. The residue is re-dissolved in THF and 108 μl (0.97 mMol) 1-methylpiperazine are added dropwise. After 2 h stirring, the mixture is diluted with EtOAc and sat. Na2CO3, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAc→EtOAc/EtOH+2% Et3N 4:1) and crystallization from EtOAc gives the title compound: m.p.: 203-204° C.; TLC(EtOAc/EtOH/NH3conc. 90:10:1): Rf=0.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=[C:48](C=CC=1)[CH2:49][N:50]1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.BrCC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:48][C:49]#[N:50])[CH2:28][CH2:27]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC#N)CC5)nc4)cnc32)cc1
Yield: 75 %

Procedure:
Using similar reaction conditions as described in step-i of example-126, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (75 mg, 0.123 mmol) was alkylated using 2-bromoacetonitrile (23 mg, 0.185 mmol) and potassium carbonate (43 mg, 0.308 mmol) in DMF (1 ml) to afford 60 mg (75.0% yield) of the titled compound. MS: m/z=647.1 (M+1).
Reaction SMILES: [ClH:1].Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH2:16][CH:15]3[CH2:17][CH:11]([CH2:12][NH:13][CH2:14]3)[CH:10]=2)[CH:4]=1.[H][H]>CO.[Pd]>[ClH:1].[ClH:1].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[CH2:16][CH:15]3[CH2:17][CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[CH:4]=1
Reactant: C1=C(c2cccnc2)CC2CNCC1C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1cncc(C2CC3CNCC(C3)C2)c1
Reaction time: 3 h

Procedure:
7-(3-pyridinyl)-3-azabicyclo[3.3.1]non-6-ene dihydrochloride (17.2 mg, 0.0629 mmol) was dissolved in methanol (10 ml), and 10% Pd/C (5 mg) was added. The mixture was hydrogenated for 3 h using a hydrogen-filled balloon. When the reaction was complete, the reaction was filtered through Celite, washed with methanol and concentrated by rotary evaporation to a light brown solid. This was dissolved in ethanol (10 ml) and treated with concentrated HCl (5 drops). The excess HCl and residual water were removed by repeated azeotropic rotary evaporation with ethanol. 7-(3-Pyridinyl)-3-azabicyclo[3.3.1] nonane dihydrochloride was isolated as a white solid (18.2 mg, 100%). GC-MS shows a 85:15 ratio of diastereomers.
Reaction SMILES: [CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1.[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH:1]([OH:3])=[O:2].[NH2:4][C:5]1[C:10]([N:11]([CH3:34])[C:12](=[O:15])[CH2:13][CH3:14])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[N:18]=[C:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[N:21]3)[N:6]=1
Reactant: CCC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: O=CO
Solvent: C1CCOC1
Product: CCC(=O)N(C)c1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 50 mg (0.11 mmol) of N-{4,6-diamino-2-[7-(2-fluorobenzyl)imidazo[1,5-b]pyridazin-5-yl]pyrimidin-5-yl}propanamide formate were initially charged in THF (0.47 ml), and 22.3 mg of a 2 N solution of sodium bis(trimethylsilyl)amide in THF (0.12 mmol) were added. After 30 min at 0° C., 14 μl (0.22 mmol) of methyl iodide were added and the mixture was stirred at 20° C. for 20 hours. The mixture was then concentrated and the residue was purified by preparative HPLC (acetonitrile/water (+0.1% formic acid) gradient). This gave 17 mg of the target compound (32% of theory).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5])[CH3:2].II.[Cl:15][C:16]1[C:17]([NH:23][NH2:24])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1.O.OO>C(O)(=O)C.CN(C)C=O>[Cl:15][C:16]1[C:17]([N:23]=[N:24][C:9]2[CH:10]=[CH:11][C:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=2[OH:12])=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=1
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CCN(CC)c1cccc(O)c1
Agent: II
Agent: OO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2ncc(Cl)cc2Cl)c(O)c1

Procedure:
Next, a flask was loaded with 3-(N,N-diethylamino)phenol (1.7 g), dimethylformamide (14 ml), acetic acid (5 ml) and iodine (0.24 g), and they were mixed, followed by addition of 3,5-dichloro-2-hydrazinopyridine (1.6 g) to the flask with stirring. Then, to this, a 30% hydrogen peroxide water (2.4 g) was dropwise added in 90 minutes and the mixture was stirred overnight. The reaction mixture was filtrated, and ether and water were added to the filtrate, followed by stirring. After stirring, the ether layer was collected and condensed to precipitate crystals. The crystals were filtrated for collection and dried to give intended crystals (0.54 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C(=O)([O-])[O-].[Na+].[Na+].F[C:20]1[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:20]1[CH:21]=[N+:22]([O-:29])[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2cc(Br)ccc2c1
Reaction time: 0.17 h
Yield: 227.1 %

Procedure:
To 6-bromo-2-naphthol (8.43 g) in 80 ml DMF at room temperature was added sodium carbonate (8.0 g) portionwise, and after the addition was complete, the mixture was stirred for 10 minutes, and then a solution of 3-fluoro-4-nitropyridine-N-oxide (6.0 g) in 40 ml DMF was added dropwise. The reaction mixture was then stirred for six hours at room temperature. The mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with sat. NaCl solution and dried over Na2SO4. The filtrate was concentrated to yield a solid (31 g). This material was triturated with methanol to yield a solid, 10.0 g, m.p. 175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([CH:13]([CH2:16][CH3:17])[CH:14]=O)[CH3:12].[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:18]1([CH:14]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[N:19]1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCC(C=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(CC)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
A suspension of 4-chlorobenzamide, 2-ethylbutanal, benzotriazole, and p-toluenesulfonic acid was processed as in Example 1C to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH2:11][OH:12])[CH2:9][OH:10])=[C:4]([F:14])[CH:3]=1.N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>CC(C)=O>[OH:12][CH2:11][C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:3][C:4]=1[F:14])([CH3:13])[CH2:9][OH:10]
Reactant: CC(CO)(CO)c1ccc(N)cc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(CO)(CO)c1ccc(NC(=O)Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred solution of 2-(4-amino-2-fluorophenyl)-2-methylpropane-1,3-diol (1.5 g, 7.53 mmol, 1.0 eq) in acetone (50 mL) was added pyridine (1.2 g, 15.18 mmol, 2.0 eq) and phenyl chloroformate (1.3 g, 8.28 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 1 h. The acetone was evaporated, and the resulting residue was diluted with EtOAc (50 mL), washed with water (100 mL), brine (20 mL) and the solvent evaporated. The crude product was purified by silica CC using EtOAc/PE (3:2) as eluent to get phenyl 4-(1,3-dihydroxy-2-methylpropan-2-yl)-3-fluorophenylcarbamate (1.7 g, 71%) as a white solid (TLC system: EtOAc/PE (7:3), Rf: 0.55).
Reaction SMILES: [CH:1]([O:3][C@H:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)[C@@H:5]([CH:19]=[O:20])[CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:2].P([O-])(O)(O)=[O:34].[Na+].Cl([O-])=O.[Na+].OO>O.C(OCC)(=O)C.C(#N)C>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:7][CH2:6][C@@H:5]([C@H:4]([O:3][CH:1]=[O:2])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:25][CH:24]=1)[C:19]([OH:34])=[O:20]
Reactant: O=P([O-])(O)O
Reactant: O=CO[C@H](CCc1ccc(C(F)(F)F)cc1)[C@@H](C=O)CCN1C(=O)c2ccccc2C1=O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=CO[C@H](CCc1ccc(C(F)(F)F)cc1)[C@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound obtained from step g above (0.22 g) in a solvent mixture of acetonitrile:water (3 mL:1 mL) at 0° C., sodium dihydrogenphosphate (0.021 g), sodium chlorite (0.081 g) and hydrogen peroxide (1 mL, 30% in water) were added. The reaction mixture was stirred for 2 hours at room temperature. The solvents were evaporated under reduced pressure to obtain a residue. Ethyl acetate and water were added to the resulting residue. The organic layer was separated, washed with water and brine, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure to afford the title compound (0.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[CH3:30]OC(OC)OC.[N-:37]=[N+:38]=[N-:39].[Na+]>C(O)(=O)C.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:30]=[N:39][N:38]=[N:37]3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(OC)OC
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3cnnn3)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Under a nitrogen atmosphere, 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11A, synthesis described in Scheme 4 where R1=4-carbamoyl-2-methylphenyl) (102 mg, 0.26 mmol) was dissolved in 2 mL glacial acetic acid. Trimethylorthoformate (0.1 mL, 0.78 mmol) was added. The mixture was stirred for 20 min. at room temperature. Sodium azide (25 mg, 0.39 mmol) was added and the reaction was heated to 80° C. for 2 hrs. After cooling, the reaction was diluted with water (3 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.5) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-tetrazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (12B) (71 mg, 60%, light orange powder).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[CH2:42][NH2:43]>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[CH2:42][N:43]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=2[NH:1][C:14]1=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2c(=O)n(Cc3ccc(OC)cc3OC)c(=O)[nH]c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution (1.5 L) of methyl 2-amino-5-ethylthiophene-3-carboxylate (30 g) in methylene chloride were added triphosgene (20.8 g) and triethylamine (58.6 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1-(2,4-dimethoxyphenyl)methanamine (48.6 mL), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (1.5 L), sodium methoxide (21.9 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with 1N hydrochloric acid and chloroform. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (55.9 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.ClC1C=CC(C(O)=O)=C(OC)C=1.S(Cl)(Cl)=O.Cl.Cl.[NH2:31][C:32]1[C:37]([NH2:38])=[CH:36][N:35]=[CH:34][N:33]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[NH2:31][C:32]1[C:37]([NH:38][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[O:11][CH3:12])=[CH:36][N:35]=[CH:34][N:33]=1
Reactant: Nc1cncnc1N
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: COc1cc(Cl)ccc1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COc1cc(Cl)ccc1C(=O)Nc1cncnc1N
Reaction time: 2 h

Procedure:
The 4-chloro-2-methoxy-benzoyl chloride prepared from 5.6 g of 4-chloro-2-methoxy-benzoic acid and 100 ml of thionyl chloride was dissolved as crude product in 100 ml of pyridine and mixed successively with 5 g of 4,5-diaminopyrimidine dihydrochloride and 1 g of 4-dimethylamino pyridine. After stirring for at first 2 hours at room termperature and then for 1.5 hours at 100° C., the reaction mixture was evaporated to dryness, mixed with water, and neutralized with sodium bicarbonate. The precipitate obtained was used in the next step without further purification.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:9])[CH2:7][SH:8].Cl[CH2:11][C:12](=[O:14])[CH3:13].O>CO>[CH3:4][O:5][C:6](=[O:9])[CH2:7][S:8][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: COC(=O)CS
Reactant: CC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CSCC(C)=O

Procedure:
To a mixture of a 5.4 M methanolic solution of sodium methylate (185 mL, 1.00 mol) in 500 mL methanol is added mercapto-acetic acid methyl ester (97.0 g, 912 mmol) at RT. After stirring for 20 minutes at RT chloro acetone (80 mL, 1.0 mmol) is added carefully. After complete addition the reaction mixture is heated at reflux for 20 minutes. The reaction mixture is added to water and extracted with diethyl ether. The organic layer is washed with brine, dried over Na2SO4 and the solvent is evaporated under reduced pressure. The crude reaction product is distilled under reduced pressure (75° C.-90° C., 0.3 mbar) yielding the desired product as colorless liquid. Yield: 61.5 g. (M+H)+=163
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br.[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[CH3:21][CH:20]([NH:23][CH2:17][CH2:18][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH3:22]
Reactant: CC(C)N
Reactant: BrCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)NCCOc1ccc(C#N)cc1

Procedure:
Following the procedure of Preparation 46, 4-cyanophenol, potassium carbonate and excess 1,2-dibromoethane was reacted and the product thereof is reacted with isopropylamine to give the title compound.