Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN1CCCC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 88.2 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.65 mmol), (prepared as described in Example 278), and pyrrolidine (0.17 ml, 2.04 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (257 mg, 88%).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37](O)=[O:38])=[C:35]([F:45])[CH:34]=1.COC[CH2:49][S:50]([NH2:53])(=[O:52])=[O:51].CS(N)(=O)=O>>[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([NH:53][S:50]([CH3:49])(=[O:52])=[O:51])=[O:38])=[C:35]([F:45])[CH:34]=1
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 64 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with methyl sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.080 g, 64%): 1H NMR (300 MHz, DMSO-d6) δ 11.82 (br s, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.83 (d, J=13.1 Hz, 1H), 4.81-4.72 (m, 1H), 3.29 (s, 3H), 2.59-2.54 (m, 1H), 2.25-2.19 (m, 1H), 2.17-2.05 (m, 1H), 2.04-1.92 (m, 1H), 1.91-1.78 (m, 1H), 1.61-1.48 (m, 1H), 1.46-1.17 (m, 4H), 0.97-0.80 (m, 3H), 0.67-0.60 (m, 2H); MS (ES+) m/z 368.09 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O1CCCC1.[S:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[N:7]1([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([NH:1][CH:23]3[CH2:24][CH2:25][S:20][CH2:21][CH2:22]3)=[CH:3][CH:4]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=C1CCSCC1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1cc(NC2CCSCC2)ccc1CN1CCOCC1
Reaction time: 8 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrahydrofuran (10 mL) and terahydrothiopyran-4-one (0.35 gm) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring overnight, the mixture is concentrated under reduced pressure. The residue is partitioned between dichloromethane and dilute aqueous sodium hydroxide. The aqueous is back-extracted with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica eluting with 2% to 6% methanol in dichloromethane and then by recrystallization from cyclohexane to afford 0.53 g of N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-thiopyran-4-amine as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:39])[CH2:24][C:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH:27]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:16]1([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH:27]=4)[CH2:24][C:23](=[O:39])[NH:22][C:9]=3[CH:10]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-4-phenylethynyl-phenyl}-carbamic acid tert-butyl ester (Example M146) (276 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (200 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1F.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: C1CNCCN1
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Br)c(N2CCNCC2)c1
Temperature: 100 °C
Yield: 30.9 %

Procedure:
A mixture of 2 g (8 mmol) 1-Bromo-2-fluoro-4-trifluoromethyl-benzene and 2.13 g (25 mmol) piperazine in 2 ml N,N-dimethylacetamide was heated to 100° C. for 2 h and subsequently all volatiles were removed under vacuum. The residue was purified by flash column chromatography on silica eluting with DCM/methanol/1% NH3 aq. to yield 0.765 g (37%) of the title compound as colourless oil.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([OH:33])(=[O:32])[CH3:31]>C(O)CCC>[CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2/[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[NH:26][C:27]/2=[O:28])[NH:13][C:12]=1[CH3:29])=[O:10])[CH2:4][CH3:5].[C:30]([O-:33])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Agent: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C
Solvent: CCCCO
Product: CC(=O)[O-]
Temperature: 20 °C

Procedure:
Sunitinib base (10 g, 0.025 mol) was suspended in 1-butanol (70 ml) with stirring at 20° C., then 1.05 eq (1.54 ml) of acetic acid were added observing dissolution and after about 5 minutes precipitation of an orange solid. The mixture was heated to 60° C. and methyl tert-butyl ether (200 ml) was added at 60° C. within 40 min with stirring, the mixture was cooled to −10° C. in 2 hours. After 16 h at −10° C. the solid was filtered, washed with 2×20 ml of MTBE and dried on filter for 1 h. 10.8 g of Sunitinib Acetate (94% yield) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[N:33]=[N:32]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:34]4[N:33]=[N:32][N:31]([CH3:30])[CH:35]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cn1cc(C(=O)O)nn1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cn(C)nn2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1-methyl-1H-1,2,3-triazole-4-carboxylic acid (19 mg, 0.15 mmol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH3:7][O:8][C:9]([C:11]#[C:12][C:13](OC)=[O:14])=[O:10]>O1CCCC1>[CH3:7][O:8][C:9]([C:11]1[N:6]2[N:5]=[CH:4][S:3][C:2]2=[N:1][C:13](=[O:14])[CH:12]=1)=[O:10]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1nncs1
Solvent: C1CCOC1
Product: COC(=O)c1cc(=O)nc2scnn12
Reaction time: 72 h

Procedure:
100 ml of tetrahydrofuran are added to 10.1 g of 2-amino-1,3,4-thiadiazole, followed by the gradual introduction of 14.2 g of acetylene dicarboxylic acid dimethyl ester. The reaction mixture is left standing for 3 days, resulting in the formation of a clear, yellow colored solution. The solution thus formed is concentrated by evaporation in vacuo to dryness. Recrystallization of the residue from ethyl acetate gives 7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester melting at 134° C. with decomposition.
Reaction SMILES: [CH:1]1([C:10]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH3:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[Li][Li].C1(C(C2C3C(=CC=CC=3)C=C2)(C)C)C2C(=CC=CC=2)C=C1.[Si:50](Cl)([CH3:53])([CH3:52])[CH3:51]>CCOCC.CCCCC>[CH3:51][Si:50]([CH3:53])([CH3:52])[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:2]2)([CH3:11])[CH3:12])[CH:14]=1
Reactant: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Reactant: C[Si](C)(C)Cl
Agent: [Li]
Agent: [Li]CCCC
Agent: [Li][Li]
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C1C=C([Si](C)(C)C)c2ccccc21)C1C=C([Si](C)(C)C)c2ccccc21

Procedure:
5.45 g (20 mmol) of 2,2-bis(indenyl)propane was dissolved in 100 ml of ether. The solution thus obtained was taken to −20° C., and 22 ml of a 2.0 M solution of n-butyl-lithium in pentane was added, thus giving a suspension of dilithium-2,2-bis(indenyl)propane. 8.77 g (30.85 mmol) of dilithium 2,2-bis(indenyl)propane was dissolved in 100 ml of ether, and 10 ml of Me3SiCl (excess) was added at a temperature of −40° C. The resulting mixture was allowed to return to room temperature. The organic phase was then separated off, the solvent removed and the product dried in vacuo.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].Cl[C:16]1[N:17]=[N:18][C:19]([I:22])=[CH:20][CH:21]=1.ClC1N=NC(Cl)=CC=1>>[I:22][C:19]1[N:18]=[N:17][C:16]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][CH:20]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Clc1ccc(I)nn1
Agent: Clc1ccc(Cl)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(I)nn1
Yield: 81 %

Procedure:
As described for example 1, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (10.0 g, 53 mmol) was converted using 3-chloro-6-iodopyridazine (Goodman, A. J.; Stanforth, S. P.; Tarbit, B. Tetrahedron 1999, 55, 15067) instead of 3,6-dichloropyridazine to the title compound (16.9 g, 81%) which was contaminated with ca. 20% of 3-chloro-6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine. The product was obtained as an off white solid. MS: m/e=394.0 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([NH2:32])[CH2:30][CH3:31])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:29]([NH:32][C:2](=[O:3])[O:4][CH3:5])[CH2:30][CH3:31])=[CH:9][CH:8]=1
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl

Procedure:
Methyl chloroformate was added to a mixture of crude 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (192 mg) and triethylamine (0.158 mL, 1.13 mmol) in tetrahydrofuran (3.5 mL) at 0° C. The resultant mixture was stirred at 0° C. for 30 min, diluted with aqueous sodium bicarbonate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 1-30% ethyl acetate/n-hexane gradient mixture and NH silica gel eluting with a 25% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (78.2 mg, 0.156 mmol).
Reaction SMILES: C([S:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[N:7][C:6]=1[CH2:5][SH:4]
Reactant: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A mixture of methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate (10.5 g, 34.39 mmol, 1.00 equiv) and potassium carbonate (12.3 g, 89.00 mmol, 2.59 equiv) in methanol (200 mL) was stirred at 35° C. under an inert atmosphere of nitrogen for 30 min. Water (200 mL) was added and the resulting solution was extracted with 3×100 mL of dichloromethane. The combined organic layers was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. To afford 8.4 g (93%) of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS-: (ES, m/z): 305 [M+CH3CN+H]+, 264 [M+H]+, 230.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[OH:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][OH:34]>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:29][OH:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: OCCNCCO
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)N(CCO)CCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 300 g. of sodium 4-acetylbenzenesulfonate is added in portions to a well-stirred, cooled solution of 500 ml. of bis(2-hydroxyethyl)amine in 750 ml. of water. The mixture is stirred at room temperature for 16 hours, cooled to 0°-5° C. and the precipitate of 4-acetyl-N,N-bis(2-hydroxyethyl)benzenesulfonamide is collected by filtration and crystallized from water; m.p. 87.5°-89.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C@@H:11]([OH:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C@@H:11]([OH:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)C(=O)N(CC(=O)O)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)[C@H](c2cc(F)cc(F)c2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of [(4S,6S)-6-(3,5-difluorophenyl)-4-hydroxy-3,3-dimethyl-2-oxopiperidin-1-yl]acetic acid (130 mg, 0.415 mmol, described in Intermediate 21), (R)-5-amino-1,3-dihydro spiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (140 mg, 0.557 mmol, described in Intermediate 9), HOBT (82 mg, 0.535 mmol), and EDC (95 mg, 0.498 mmol) in DMF (2 mL) was stirred at ambient temperature for 6 h. The reaction mixture was partitioned between H2O (50 mL), saturated aqueous NaHCO3 (30 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 90:10, to give the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2169; calculated m/z=547.2151 for C30H29F2N4O4.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[CH2:23][N:24]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C>[NH2:24][CH2:23][C:3]1[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)=[N:5][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:7][C:2]=1[CH3:1]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN
Yield: 22.8 %

Procedure:
A suspension of 6-methyl-4-(3-nitrophenyl)-5-phthalimidomethyl-2-phenylpyrimidine (6.9 g) and hydrazine monohydrate (0.8 g) in ethanol (140 ml) was refluxed for 6 hours. After filtering off the insolubles, the filtrate was poured into a suspension of chloroform (200 ml) and water (300 ml) under stirring. The organic layer was separated, washed with aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo and the resulting crystals were recrystallized from ethanol to give 5-aminomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.12 g).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH3:11]Br>O1CCCC1>[CH3:11][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: CBr
Reactant: Oc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with methyl bromide yielding para-methoxyphenol. The para-methoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-methoxytosyloxybenzene. The para-methoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-methoxy-3-iodo-1-tosyloxybenzene. The 4-methoxy-3-iodo-1-tosyloxybenzene can be extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-methoxy-3-iodophenol. The 4-methoxy-3-iodophenol can be extracted and exposed to resin-bound triphenyphosphine (PPh3) in a solution of azopyridine and ethanol (CH3CH2OH) in a salt bath at 0° C., yielding 4-ethoxy-2-iodomethoxybenzene. The 4-ethoxy-2-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-ethoxy-4-iodo-5-methoxybenzaldehyde. The 2-ethoxy-4-iodo-5-methoxybenzaldehyde can be added to lithium aluminum hydride (LiAlH4) and methanesulfonyl chloride (CH3SO2Cl) dissolved in pyridine, and then sodium iodide (NaI) and triethyl phosphite (P(OCH2CH3)3) can be added to the reaction mixture, yielding diethyl 2-ethoxy-4-iodo-5-methoxybenzylphosphonate.
Reaction SMILES: [ClH:1].[C:2](#[N:7])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([OH:10])[CH3:9]>>[ClH:1].[CH2:8]([O:10][C:2](=[NH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH3:9]
Reactant: CCO
Reactant: CCCCC#N
Agent: Cl
Product: CCCCC(=N)OCC
Temperature: 0 °C
Reaction time: 144 h

Procedure:
Hydrogen chloride gas was bubbled into a tared solution of valeronitrile (92.0 g, 1.08 mole) in absolute ethanol (64 ml, 1.08 mole) in a 1-liter round bottom flask cooled to 0° C. The flask was weighed periodically and hydrogen chloride gas bubbling was continued until the weight gain was greater than 39 g (1.08 mole). The mixture was then stoppered and stored at 0° C. for 6 days. Ether (650 mi) was then added (cold) and the mixture was stored at -30° C. for 24 hours. The resulting solid was collected on a buchner funnel, transferred quickly to a large beaker, triturated quickly with cold ether, and collected again on a buchner funnel. The solid was then dried in vacuum to give the title F compound as a free flowing white solid (95 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH:26][C:24](=[NH:25])[CH2:23][O:22][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)=[O:6]
Reactant: O=C(O)c1cc(Cl)cnc1Cl
Reactant: N=C(N)COCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N=C(COCCc1ccc(Cl)cc1)NC(=O)c1cc(Cl)cnc1Cl

Procedure:
In analogy to the procedure described in example 78.3, 2,5-dichloronicotinic acid was reacted with 2-[2-(4-chloro-phenyl)-ethoxy]-acetamidine hydrochloride in the presence of TBTU and DIPEA to give 2,5-dichloro-N-{2-[2-(4-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide as yellow oil. MS: m/e=388.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][O:20]C(=O)C)[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26].C[O-].[Na+].CO.O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14])[C:6]([Br:24])=[C:5]2[CH:25]=[O:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)c(C=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=Cc1c(Br)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
5,6-Dichloro-2-bromo-3-formyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.136, 101 mg, 0.22 mmol) was dissolved in dry MeOH (10 mL) to which was added sodium methoxide (25 mg, 0.46 mmol). The solution was stirred at room temperature for 15 min, until the starting material was consumed (TLC). Water (30 mL) was added and the solution evaporated until the MeOH was completely removed. The residual aqueous suspension was extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine (20 mL), dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a white solid which was recrystallized from MeOH and H2O to yield 43 mg (47%) of 4.137 as a pale tan powder: mp 210-211° C.; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.95 (s, 1H), 8.69 (s, 1H), 8.28 (s, 1H), 6.06 (d, 1H), 5.49-5.43 (m, 2H, D2O exch.), 5.31 (d, 1H, D2O exch.), 4.44 (q, 1H), 4.18 (m, 1H), 4.04 (d, 1H), 3.77-3.71 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 185.53, 134.05, 128.85, 126.58, 126.47, 125.31, 120.56, 116.00, 114.68, 90.27, 86.55, 71.69, 69.62, 60.98. HRMS (EI) m/z calcd. for C14H12BrCl2NO5 422.9276. found 422.9271. Anal calcd for C14H12BrCl2NO5: C, 39.56; H, 2.85; N, 3.30. Found: C, 39.77; H, 3.03; N, 3.32.