Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=[CH2:3].[C:36](Cl)(=[O:38])[CH3:37].C(N(C(C)C)CC)(C)C>ClCCCl>[C:36]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C@@H:24]([N:6]2[C@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C@@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[CH2:9][C@@:4]([CH2:1][CH:2]=[CH2:3])([CH3:35])[C:5]2=[O:34])[CH2:32][CH3:33])[CH2:31][CH2:30]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCNCC2)C1=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(C(C)=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B) (80 mg, 0.155 mmol) in DCE (1.5 mL) was added acetyl chloride (22.1 μL, 0.31 mmol) followed by diisopropylethylamine (54.1 μL, 0.311 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl.Cl[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:23])=[C:11]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[CH:18][N:17]=3)=[O:15])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: ClCc1ccccn1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cn1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cn1

Procedure:
The title compound was prepared from N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5 -hydroxypyridine-2-carboxamide and 2-chloromethyl-pyridine hydrochloride according to the method described for Example 4; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.40 (s, 2H), 7.33 (m, 1H), 7.39 (m, 1H), 7.58 (m, 2H), 7.72 (m, 1H), 7.88 (m, 1H), 8.13 (m, 1H), 8.21 (m, 1H), 8.36 (m, 1H), 8.51 (m, 1H), 8.61 (m, 1H), 10.14 (s, 11H); Mass Spectrum: M+H+ 403.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)N2CCOCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(morpholine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using morpholin-4-carbonyl chloride instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 496.2 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[C@@H:4]([NH:32][C@@H:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[CH2:43]=O>>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:43][N:32]1[C@@H:33]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:34][CH3:35])=[O:42]
Reactant: C=O
Reactant: CC[C@@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)c1ccccc1
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-((R)-1-phenyl-propylamino)-propionic acid methyl ester (0.165 g) was treated with formaldehyde according to General Procedure V to give (3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (0.13 g). This was treated with LiOH in THF:MeOH (1:3) according to General Procedure B to give (3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-7-((R)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (75 mg). LCMS (m/z): 604
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=1>>[OH:4][CH2:3][CH2:2][NH:1][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][N:7]=1
Reactant: NCCO
Reactant: O=Cc1ccc(Cl)nc1
Product: O=Cc1ccc(NCCO)nc1
Temperature: 135 °C
Reaction time: 14 h

Procedure:
10.12 g (165.68 mmol) of 2-aminoethanol are added to 1.00 g (7.06 mmol) of 6-chloronicotinaldehyde, and the reaction mixture is then stirred at 135° C. for 14 h. This gives a yellow solution which is fractionated by distillation in a kugelrohr apparatus (2.2 mbar, 100° C.). The fraction comprising the desired product is then directly reacted further.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9]([C:11]1[C:20]2[O:21][C:22]3([C:32]([CH3:34])([CH3:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]3[CH3:35])[CH:23]=[N:24][C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)=O>N1CCCCC1.C(O)C>[C:1]([C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:11]1[C:20]2[O:21][C:22]3([C:32]([CH3:33])([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]3[CH3:35])[CH:23]=[N:24][C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)#[N:2]
Reactant: CN1c2ccccc2C(C)(C)C12C=Nc1c(c(C=O)cc3ccccc13)O2
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1cc2ccccc2c2c1OC1(C=N2)N(C)c2ccccc2C1(C)C
Temperature: 60 °C

Procedure:
To a solution of 0.18 g (1.5 mmol) of ethyl cyanoacetate in a minimum quantity of ethanol are added 0.36 g (1 mmol) of the product of Example 1 and then two drops of piperidine. The mixture is heated at 60° C. until a precipitate appears. The precipitate obtained is filtered off, washed with ethanol and dried.
Reaction SMILES: [C:1]1([C:7]2[CH2:12][O:11][CH2:10][CH2:9][C:8]=2[CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl>[Br:15][CH2:13][C:8]1[CH2:9][CH2:10][O:11][CH2:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1=C(c2ccccc2)COCC1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: BrCC1=C(c2ccccc2)COCC1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of (5-phenyl-3,6-dihydro-2H-pyran-4-yl)methanol (360 mg, 1.89 mmol) in DCM (6 mL) was added dibromotriphenylphosphorane (880 mg, 2.08 mmol) at room temperature, after stirring for 30 min, it was diluted with DCM, organic layer was washed with Sat. NaHCO3, brine, dried and concentrated to give crude product, which was purified by column(Hexanes/EtOAc=9:1) to give 4-(bromomethyl)-5-phenyl-3,6-dihydro-2H-pyran (380 mg).
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]=O>C(O)C.O>[CH:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:23]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNC2CCCCC2)c(Cl)c1
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CN(C3CCCCC3)CC2=O)c(Cl)c1

Procedure:
2-Cyclohexylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (17.2g) was dissolved in ethanol (150 ml) and paraformaldehyde (3g) in water (300 ml) added. The mixture was refluxed 2 hrs, cooled and filtered. The residue was crystallised from ethanol/petroleum ether. Yield 13.5 g, m.p. 188°-190° .
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Cl:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:25][N:26]([CH3:33])[CH2:27][CH:28]=[CH:29][C:30](Cl)=[O:31]>>[Cl:23][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH:3]=[CH:4][C:5]=3[CH3:24])[CH:14]=2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: CN(C)CC=CC(=O)Cl
Reactant: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Product: Cc1ccc(NC(=O)/C=C/CN(C)C)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1

Procedure:
N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine (Int-F) and 4-dimethylamino-2-butenoyl chloride were combined in a manner similar to that described in Scheme 4a to give (E)-N-[3-(6-{3-chloro-4-fluorophenyl}amino-pyrimidin-4-ylamino)-4-methylphenyl]-4-(dimethylamino)but-2-enamide (I-54). MS (m/z): 455/457 (M+1, 100/39%). 1H NMR (DMSO-d6) δ 11.02 (bs, 1H), 10.66 (bs, 1H), 9.92 (bs, 1H), 9.39 (bs, 1H), 7.92-7.94 (m, 1H), 7.75 (bs, 1H), 7.27-7.56 (m, 4H), 6.80 (m, 1H), 6.54 (d, 1H), 5.89 (bs, 1H), 3.92 (bs, 2H), 2.75 (bs, 6H), 2.17 (bs, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C=O)C>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:11][CH:10]=2)[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][C:7]1=[O:13]
Reactant: O=C=Nc1ccccc1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(NC(=O)Nc3ccccc3)ccc21
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A solution of 6-amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 48 mg, 200 μmol) in anhydrous DMF (2 mL) was treated with PhNCO (33 μL, 300 μmol) & pyridine (16 μL, 20 μmol). The mixture was stirred for 16 h & then partitioned between EtOAc (30 mL) & H2O (20 mL). The organic layer was washed with H2O (20 mL) & brine (20 mL), before being dried (MgSO4). After filtration, the solution was concentrated & a precipitate formed. This precipitate was collected by filtration & washed with cold EtOAc to give the title compound (58 mg, 80%): δH ((CD3)2SO)=3.60 (s, 3H), 7.00 (t, 1H), 7.10 (s, 1H), 7.30 (t, 2H), 7.45 (d, 2H), 7.65 (d, 1H), 7.75 (dd, 1H), 8.15 (d, 1H), 8.70 (s, 1H), 9.00 (s, 1H); m/z (ES+)=362.2
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[CH:3]=1.[BrH:16].O.N>O>[NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[C:3]=1[Br:16]
Reactant: Br
Reactant: Nc1ccc2c(ccc3ccccc32)c1
Agent: N
Solvent: O
Product: Nc1ccc2c(ccc3ccccc32)c1Br
Temperature: 25 °C
Yield: 89.5 %

Procedure:
First, 10.0 g of 2-aminophenanthrene were dissolved in 75 mL of N,N-dimethyl sulfoxide, and then 8.3 g of 48% hydrobromic acid were dropped to the solution over 4 hours while the solution was stirred at room temperature. The mixture was continuously stirred at room temperature for 20 hours, and was then stirred at 100° C. for 1 hour under heat. After having been cooled to room temperature, the reaction solution was poured into 300 mL of water. After the mixed solution had been neutralized with ammonia water, the crystal was separated by filtration. The resultant solid was recrystallized with ethanol and water. Thus, 12.6 g of a colorless crystal were obtained (in 90% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH2:33]O)[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:35])[CH2:3][CH2:2]1.C(N(S(F)(F)[F:43])CC)C.O>ClCCl>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH2:33][F:43])[CH:19]=[C:20]([NH:21][CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:35])[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(-c4ccccc4CO)nn23)ccc1C(=O)NC1CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2cnc3c(NCC(C)(C)O)cc(-c4ccccc4CF)nn23)ccc1C(=O)NC1CC1
Reaction time: 0.17 h
Yield: 8 %

Procedure:
To a solution of 329 mg (677 μmol) N-cyclopropyl-4-{6-[2-(hydroxymethyl)phenyl]-8-[(2-hydroxy-2-methylpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide which was prepared according to example 220 in 13 mL dichloromethane at 3° C. were added 98 μL N-ethyl-N-(trifluoro-lambda4-sulfanyl)ethanamine. After stirring for 10 minutes, the solution was poured into water and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with sodium hydrogencarbonate solution and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 28.6 mg (8%) of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Cl:10].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:6]=[O:7]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1Cl
Temperature: 90 °C

Procedure:
To a solution containing 1.0 g 4-fluoro-3-chlorobenzaldehyde and 45 ml DMSO, was added 1.93 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 1.06 g. 1H-NMR (DMSO-d6, 400 MHz): 3.45 (s, 3H, CH3), 8.09-8.27 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).
Reaction SMILES: [N:1](OCCCC)=O.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[CH3:18])([O-:10])=[O:9].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:18]#[N:1]
Reactant: CCCCON=O
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc([N+](=O)[O-])c1C#N
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A solution of 16 g (150 mmol) of n-butyl nitrite (97%) and 7.7 g (50 mmol) of 3-nitro-o-xylene (97%) in 50 ml of dimethylformamide is cooled to from −5 to −10° C., and a solution of 11 g (100 mmol) of potassium tert-butoxide in 50 ml of dimethylformamide is added at this temperature, over a period of 1.5 hours. The reaction mixture is stirred at room temperature for another 6 days. For work-up, the mixture is poured onto ice-water and adjusted to pH 1 using hydrochloric acid, and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and concentrated. This gives 8.2 g of product. The 2-methyl-6-nitrobenzonitrile can be purified by silica gel chromatography using the mobile phase toluene. M.p.: 101-103° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[C:24](=[CH2:26])[CH3:25]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:25][C:24]([CH3:26])=[CH2:23])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: C=C(C)C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=C(C)Cc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Temperature: 130 °C
Reaction time: 0.75 h
Yield: 45.1 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (301.5 mg, 0.80 mmole), methallyltri-n-butyltin (529 μl, 1.60 mmole) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmole) in dimethylformamide (4 ml) was stirred at 130° C. for 45 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (128 mg). MS: (+) m/z 355.02 (M+1).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[N:12][C:11]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Li]CCCC.CCCCCC.[Cl:41][C:42]1[CH:59]=[CH:58][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]=[O:57])=[CH:48]2)=[CH:44][CH:43]=1>C1COCC1>[Cl:41][C:42]1[CH:43]=[CH:44][C:45]([CH2:46][N:47]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]([CH:56]([C:13]3[N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:29])=[CH:2][CH:3]=4)(=[O:9])=[O:8])=[C:11]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:12]=3)[OH:57])=[CH:48]2)=[CH:58][CH:59]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)ncn2COCC[Si](C)(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)nc(C(O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)n2COCC[Si](C)(C)C)cc1
Reaction time: 0.33 h
Yield: 26.6 %

Procedure:
To a stirred solution of 2-[5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-pyridine (0.15 g, 0.35 mmol) in dry THF (10 mL) was added 2.5 M n-BuLi solution in hexane (0.21 mL, 0.525 mmol) under N2 at −78° C. After 20 minutes at this temperature, a solution of N-4-chlorobenzylindole-3-carboxaldehyde (0.1 g, 0.37 mmol) in dry THF (3 mL) was then added through a cannula. Stirring was continued at this temperature for 1 hour. The reaction was then quenched with H2O (10 mL) at 0° C. The aqueous solution was extracted with dichloromethane (3×15 mL). Combined dichloromethane solution was washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the crude material was separated by silica gel chromatography (2:1 hexane/ethyl acetate to 2:1 ethyl acetate/hexane) to afford the desired intermediate [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol as an oil (65 mg, 30%). 1H NMR (CDCl3) δ −0.05 (s, 9H), 0.70 (t, 2h, J=6), 2.55 (s, 3H), 3.2–3.35 (m, 2H), 4.02 (d, 1H, J=7), 5.2–5.4 (m, 2H), 5.41 (s,2H), 6.4 (d, 1H), 7.0–8.0 (m, 16 H), 8.8 (d, 1H J=5). ESMS calcd for (C37H39ClN4O4SSi): 698.6; found: 699.6 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C[O-].[Na+]>>[Cl:1][C:2]([Cl:7])([CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cl
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CCC(Cl)(Cl)C(=O)OC

Procedure:
reacting methyl dichloroacetate and acrylic acid methyl ester with sodium methoxide to obtain Dimethyl 2,2-dichloroglutarate;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH:16]=[CH2:17])[CH:9]=1.[CH3:26][C@H:27]([CH:31]=[CH2:32])[C:28](O)=[O:29].N1C=CC=CC=1>CCOC(C)=O>[CH3:26][C@H:27]([CH:31]=[CH2:32])[C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH:16]=[CH2:17])[CH:9]=1)=[O:29]
Reactant: C=C[C@@H](C)C(=O)O
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2N)ccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2NC(=O)[C@H](C)C=C)ccn1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a solution of 45D (1.4 g, 4.12 mmol), (R)-2-methylbut-3-enoic acid (0.58 g, 5.79 mmol) in EtOAc (41.2 ml) was added pyridine (1.001 ml, 12.37 mmol). The reaction was cooled down to 0° C. under Ar and propane phosphonic acid anhydride (4.91 ml, 8.25 mmol) was added dropwise. The reaction was then gradually warmed up to rt over night. The reaction mixture was diluted and washed with sat. aq. NaHCO3, aqueous layer back-extracted with EtOAc, combined EtOAc phase washed with brine, dried over MgSO4, filtered, concentrated. The residue was purified by silica gel chromatography to give the desired product (1.47 g, 85%) as an off white foam. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.65-8.60 (m, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.47-7.36 (m, 2H), 7.24-7.18 (m, 3H), 7.16 (dd, J=5.0, 1.4 Hz, 1H), 5.82-5.62 (m, 3H), 5.10-5.01 (m, 4H), 4.86 (d, J=7.2 Hz, 1H), 3.03 (quin, J=7.2 Hz, 1H), 2.62 (tq, J=14.1, 6.9 Hz, 2H), 1.49-1.36 (m, 9H), 1.25 (d, J=7.2 Hz, 3H). MS (ESI) m/z: 422.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:11]4([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CN1OC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCCOC3)Oc3ccc(-c4cccc(F)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (40 mg, 0.1 mmol) in 1,4-dioxane (2 mL), Cs2CO3 (2 N, 0.4 mL) and 3-fluorophenylboronic acid (29.3 mg, 0.2 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and then by preparative HPLC to give pure product 6-(3-fluorophenyl)-2′-methyl-2-(tetrahydro-2H-pyran-3-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (5 mg, 10%). 1H-NMR (MeOD): 1.70 (m, 3H), 2.01 (m, 3H), 2.49 (m, 0.5H), 2.71 (m, 1H), 3.32 (d, 3H), 3.43 (m, 1H), 3.53 (m, 1H), 3.91 (dd, 2H), 4.19 (m, 2H), 7.03 (m, 2H), 7.32 (d, 1H), 7.43 (m, 2H), 7.66 (t, 1H), 7.89 (s, 1H).