Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][C:16]=2[O:27][CH3:28])[C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.C(N(CC)CC)C.Cl.Cl[CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>O1CCCC1>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:43][CH2:44][N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[CH2:23][CH2:22]3)=[CH:17][C:16]=2[O:27][CH3:28])[C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: COc1cc(N2CCNCC2)ccc1Nc1cc(Cc2c(F)cccc2Cl)cnc1C(N)=O
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(N2CCN(CCN3CCOCC3)CC2)ccc1Nc1cc(Cc2c(F)cccc2Cl)cnc1C(N)=O

Procedure:
A solution of EXAMPLE 42B (25 mg, 0.053 mmol) in tetrahydrofuran (1 mL), triethylamine (22.24 uL, 0.16 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (9.9 mg, 0.053 mmol) were heated to 75° C. over 18 hours. The reaction mixture was concentrated under reduced pressure and purified on RP-HPLC (10 mM ammonium acetate/acetonitrile) to afford the title compound. 1H NMR (CDCl3) δ ppm 9.76 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.23-7.06 (m, 4H), 7.06-6.91 (m, 1H), 6.58-6.53 (d, J=2.5, 6H), 6.47 (dd, J=8.6, 2.5, 5H), 5.46 (s, 1H), 4.02 (d, J=1.9, 2H), 3.83-3.68 (m, 7H), 3.27-3.09 (m, 4H), 2.77-2.49 (m, 12H); MS (ESI) m/z 584 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([CH:27]=[O:28])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:36]1[CH:37]=[CH:38][C:39]([C:44]([F:47])([F:46])[F:45])=[C:40]([CH:43]=1)[C:41]#[N:42].C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:12]([C@@H:27]([OH:28])[C:36]3[CH:37]=[CH:38][C:39]([C:44]([F:45])([F:46])[F:47])=[C:40]([CH:43]=3)[C:41]#[N:42])=[C:11]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: N#Cc1cc(I)ccc1C(F)(F)F
Reactant: CC1(C)Cc2nc(C3CCOCC3)c(C=O)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@@H](O)c3ccc(C(F)(F)F)c(C#N)c3)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-iodo-2-(trifluoromethyl)benzonitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[N:12]([CH3:24])[C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Yield: 129.5 %

Procedure:
A solution of 7.5 grams (0.021 mole) of 3-(3-amino4-chloro-6-fluoro-2-methoxyphenyl)-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, 3.4 grams (0.025 mole) of potassium carbonate, and 3.5 grams (0.025 mole) of methyl iodide in 200 mL of acetone was stirred at ambient temperature for about 18 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in 200 mL of water. The mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 6.9 grams of crude product. The dark oil was combined with 7.0 grams of crude product prepared by a similar route to yield a total of 13.9 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 10.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:19][C@H:18]2[C@H:14]([N:15]=[C:16]([N:20]([CH3:22])[CH3:21])[S:17]2)[C@@H:13]([OH:23])[C@@H:12]1[OH:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH3:26][C:27]1C=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C>CN(C=O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:12]2[C@H:13]([O:23][C:27]([CH3:28])([CH3:26])[O:24]2)[C@@H:14]2[C@@H:18]([S:17][C:16]([N:20]([CH3:21])[CH3:22])=[N:15]2)[O:19]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Agent: C=C(C)OC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1=N[C@@H]2[C@H]3OC(C)(C)O[C@@H]3[C@@H](COC(=O)c3ccccc3)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a solution of 154 (3.0 g, 8.5 mmol) in DMF (20 mL) was added 4-methylbenzenesulfonic acid hydrate (3.2 g, 17 mmol) and 2-methoxyprop-1-ene (6.1 g, 85 mmol) sequentially. The resulting solution was stirred for 15 minutes at room temperature, before the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL), which was then extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (2×10 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography with 1%-10% ethyl acetate in petroleum ether to afford 155 as an off-white solid (1.6 g, 48%). (ES, m/z): [M+H]+ 393.0; 1H NMR (300 MHz, CDCl3) δ 8.08-8.05 (m, 2H), 7.63-7.45 (m, 3H), 6.32-6.30 (m, 1H), 4.60-4.52 (m, 2H), 4.41-4.31 (m, 2H), 3.97-3.91 (m, 1H), 3.70-3.63 (m, 1H), 3.55-3.50 (m, 1H), 3.39-3.30 (m, 1H), 3.10 (s, 6H), 1.50 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:20]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:33](=[O:43])[C@H:34]([CH2:38][S:39](Cl)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:33](=[O:43])[C@H:34]([CH2:38][S:39]([N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[N:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][N:10]=2)[CH2:15][CH2:16]1)(=[O:41])=[O:40])[CH:35]([CH3:37])[CH3:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1ccc(-c2cnc(C3CCNCC3)nc2)cc1
Reactant: CC(C)[C@@H](CS(=O)(=O)Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 100.1 %

Procedure:
Prepared according to the method for the preparation of 4-(R)-benzyl-3-(2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-ulfonylmethyl}-3-methyl-butyryl)oxazolidin-2-one, from 5-(4-chlorophenyl)-2-piperidin-4-ylpyrimidine (0.123 g) and 4-(R)-benzyl-3-(2-(R)-chlorosulfonylmethyl-3-methylbutyryl)-oxazolidin-2-one (0.269 g), to yield the title compound as a cream foam (0.275 g, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:20]([O:19][C:17]([C@@H:2]([NH:1][S:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:36])[F:37])=[CH:31][CH:30]=1)(=[O:34])=[O:33])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
210.5 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 269 mg of 4-trifluoromethylbenzenesulfonyl chloride and 284 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 66 mg. MS (ES+): m/e=532.2 (M+H)+; 476.1.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][N:13]2[C:17]([CH3:18])=[C:16]([Cl:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14]2)[CH2:7][CH2:6]1)=[O:4].CCO.[OH-].[Na+]>O>[Cl:19][C:16]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:14][N:13]([CH2:12][C:11]([N:8]2[CH2:7][CH2:6][C:5]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[O:24])[C:17]=1[CH3:18]
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)Cn2nc(C(F)(F)F)c(Cl)c2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1

Procedure:
In a 4 mL vial was added 100 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester (0.21 mmol, 1.0 equiv) and 400 mL EtOH. A solution of 9.2 mg of NaOH (0.23 mmol, 1.10 equiv) dissolved in 100 μL H2O was added to the reaction solution and the resultant mixture was stirred overnight at room temperature. The crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carboxylic acid: MS (ES) M+H expected=464.3, found=464.1.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])/[CH:10]=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:27][C:28]1[CH:33]=[C:32]([CH2:34]Br)[CH:31]=[CH:30][C:29]=1[F:36]>>[Br:27][C:28]1[CH:33]=[C:32]([CH2:34][C@H:10]([NH:11][S@:12]([C:14]([CH3:15])([CH3:16])[CH3:17])=[O:13])[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH:31]=[CH:30][C:29]=1[F:36]
Reactant: Fc1ccc(CBr)cc1Br
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1ccc(F)c(Br)c1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared from (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide and 2-bromo-4-(bromomethyl)-1-fluorobenzene using a method analogous to that described in Examples 509 and 510.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Product: CC(=O)Nc1ccc(OCCn2c(C)cc3c(Cl)c(C#N)ccc32)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and N-{4-[(2-bromoethyl)oxy]phenyl}acetamide: 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.89 (d, J=1.1 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.39 (d, J=8.9 Hz, 2H), 6.73 (d, J=8.9 Hz, 2H), 4.62 (t, 2H), 4.19 (t, 2H), 2.48 (s, 3H), 1.95 (s, 3H); MS (ES) m/z 368 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14](=[O:15])[C:13]2[N:12]=[C:11]([CH:16]=O)[CH:10]=[CH:9][C:8]=2[C:7](=[O:18])[CH:6]=1)(=[O:3])[CH3:2].[CH2:19]([O:24][C:25](=[O:38])[C@H:26]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH2:27])[CH2:20][CH:21]([CH3:23])[CH3:22]>C1(C)C(C)=CC=CC=1>[CH3:23][CH:21]([CH2:20][CH2:19][O:24][C:25]([C:26]1[CH:28]=[C:29]2[C:30](=[C:16]([C:11]3[CH:10]=[CH:9][C:8]4[C:7](=[O:18])[CH:6]=[C:5]([NH:4][C:1]([CH3:2])=[O:3])[C:14](=[O:15])[C:13]=4[N:12]=3)[N:27]=1)[NH:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:37]2=1)=[O:38])[CH3:22]
Reactant: CC(=O)NC1=CC(=O)c2ccc(C=O)nc2C1=O
Reactant: CC(C)CCOC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1C
Product: CC(=O)NC1=CC(=O)c2ccc(-c3nc(C(=O)OCCC(C)C)cc4c3[nH]c3ccccc34)nc2C1=O
Yield: 429 %

Procedure:
7-Acetamido-2-formylquinoline-5,8-dione (23) (prepared as described in Example 23) (244 mg, 0.1 mmol), L-tryptophan isoamyl ester (37) (prepared as described in Example 37) (239 mg, 1 mmol) and xylene (64 ml) were mixed. The mixture was stirred and slowly heated in an oil bath from room temperature to 110° C. over a one-hour period, and then from 110° C. to 140° C. over a 3-hr period. The hot reaction mixture was filtered to remove the brown impurity. The filtrate was evaporated under vacuum. The residue was treated with ethyl-acetate/hexane to give an orange solid (213 mg, 42% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:23]([O:25]CC)=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:11].CCN(C(C)C)C(C)C>CO>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:13]1[NH:12][C:10](=[O:11])[CH2:9][NH:8][C:23]1=[O:25]
Reactant: CCOC(=O)[C@H](Cc1cccc(OC)c1)NC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1cccc(CC2NC(=O)CNC2=O)c1
Temperature: 75 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-methoxyphenylalaninate trifluoroacetate (598 mg, 2.13 mmol), Hünig's base (0.371 mL, 2.13 mmol), and MeOH (20 mL). The reaction mixture was stirred at 75° C. for 24 h. The mixture was allowed to cool to room temperature. The solid formed was collected by filtration and washed with MeOH to give 3-(3-methoxybenzyl)-2,5-piperazinedione (423 mg).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:30])[C@@H:3]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[N:9]=[CH:8]2.C(N(CC)CC)C.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>ClCCl>[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43]([NH:1][C@@H:2]([CH3:30])[C@@H:3]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)[N:9]=[CH:8]2)=[O:44]
Reactant: COC(=O)c1ccc(-n2ncc3cc(O[C@H](c4ccccc4)[C@H](C)N)ccc32)cc1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-n2ncc3cc(O[C@H](c4ccccc4)[C@H](C)NC(=O)c4ccco4)ccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.2 %

Procedure:
Methyl 4-{5-[(1R,2S)-2-amino-1-phenylpropoxy]-1H-indazole-1-yl}benzoate (64.3 mg, 0.16 mmol) is dissolved in 6.1 mL of dichloromethane. Triethylamine (0.053 mL, 0.38 mmol) and 2-furoylchloride (20.9 mg, 0.16 mmol) are added. After 4 h stirring at r.t. the reaction mixture is diluted with dichloromethane, washed with water and brine and dried over Na2SO4. The reaction mixture is filtered, the solvent evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 38.2 mg (48.1%) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>CC(O)=O.CS(C)=O>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:30][C:29]2[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[CH:10][C:11]3[CH:16]=[N:15][C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:13][C:12]=3[N:28]=2)=[O:40])=[CH:34][CH:33]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccc(Br)cc4)nc3n2)CC1
Yield: 67.7 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.44 g of 4-bromophenyl isocyanate according to the general procedure of Example 37 to give 0.97 g of 1-(4-Bromo-phenyl)-3-{6-(2,6-dichlorophenyl)-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-urea, ESMS (20/80 MeOH/CH3 CN+0.1% AcOH+DMSO): M+ +H=645; mp 171°-175° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:3]4[O:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1ccoc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A dry flask was charged with 3-Methyl-furan-2-carboxylic acid (0.500 g, 3.96 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (40 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.00 g, 3.96 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.242 g, 3.45 mmol, 87%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[N:9]=2)[CH2:4][CH2:3]1.C(O)C>[Pd].C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[C:10]([CH2:17][S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)n2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(CS(=O)(=O)c3ccccc3)n2)CC1
Yield: 99 %

Procedure:
A mixture of 1-methyl-4-{5-nitro-6-[(phenylsulfonyl)methyl]pyridin-2-yl}-piperazine (1.60 g, 4.35 mmol) and 10% Pd/C (200 mg) in a 1:1 mixture of ethanol:THF is hydrogenated at 45 psi for 4 h at ambient temperatures. The catalyst is filtered off and the filtrate is concentrated in vacuo to afford the title compound as a yellow solid, 1.45 g (99% yield), identified by NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: [H][H]
Reactant: O=C1CCC(=Cc2cc(Cl)cc(Cl)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: OC1CCC(Cc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 60 h
Yield: 90.9 %

Procedure:
A mixture of 7.5 grams (0.031 mole) of 4-(3,5-dichlorophenylmethylene)cyclohexanone and 1.0 gram (catalyst) of 10% palladium on charcoal (Degussa type) in 100 mL of ethanol was placed in a hydrogenation bottle and hydrogenated using a Parr hydrogenation apparatus. Upon completion of 2 hours at 50 psi, the reaction had used 25% of the theoretical amount of hydrogen. After this time the reaction mixture was filtered, and an aliquot was concentrated under reduced pressure to a residue. An NMR spectrum indicated that complete hydrogenation had not taken place. The hydrogenation was again conducted using the cyclohexanone above, and 1.0 gram of fresh 10% palladium on charcoal in 100 mL of ethanol. Upon the uptake of the theoretical amount of hydrogen, the reaction mixture was filtered. The filtrate was allowed to stand about 60 hours and then was concentrated under reduced pressure, yielding 7.3 grams of 4-(3,5-dichlorophenylmethyl)cyclohexanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([N+:10]([O-:12])=O)[C:3]=1[NH2:4].[N:13]#[C:14][NH2:15]>C(O)(=O)C.Cl>[NH2:15][C:14]1[N:13]=[N+:10]([O-:12])[C:5]2[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([Br:1])[C:3]=2[N:4]=1
Reactant: N#CN
Reactant: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(Br)c2nc(N)n[n+]([O-])c2c1
Temperature: 50 °C
Yield: 51.5 %

Procedure:
To 13.0 g (56.3 mmol) of 2-bromo-4-methyl-6-nitroaniline stirring in a mixture of 25 ml glacial acetic acid and 5 ml of concentrated hydrochloricacid at 80° C., 29.0 g (690.5 mmol) of cyanamide and 25 ml of concentrated hydrochloric acid were added simultaneously, separately, and very slowly. At one point during the addition, a vigorous exotherm occurred and the external heat immediately removed. After the addition, the reaction was heated at reflux for 15 minutes. On cooling to about 50° C., 100 ml of 25% aqueous sodium hydroxide were added dropwise and the mixture heated at reflux 15 minutes. The reaction was cooled to room temperature, the insoluble orange solid filtered and washed with water followed by ethyl acetate to afford 7.4 g of yellow 3-amino-5-bromo-7-methyl-1,2,4-benzotriazine-1-oxide after drying.