Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C(C=C)=O)C.ClC1C(C)=C(C=CC=1)N.C([C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](Cl)[C:22]=2C)C.C(C1CC2C(=C(C)C(Cl)=CC=2)NC1)C>>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:18][CH:19]=1
Reactant: CCc1cnc2c(C)c(Cl)ccc2c1
Agent: C=CC(=O)CC
Agent: CCC1CNc2c(ccc(Cl)c2C)C1
Agent: Cc1c(N)cccc1Cl
Product: c1ccc2ncccc2c1
Yield: 60 %

Procedure:
The procedure described in Example 1 was followed, except that 187 g/hour of ethylacrolein and 283 g/hour of 3-chloro-2-methylaniline were employed. Distillation gave 335 g of distillate at a boiling point of 125° C./2 mm Hg. This distillate contained 75% by weight of 3-ethyl-7-chloro-8-methylquinoline and 22% by weight of 3-ethyl-7-chloro-8-methyltetrahydroquinoline, corresponding to a quinoline yield of 60%, based on 3-chloro-2-methylaniline employed.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.Cl.CCN=C=NCCCN(C)C>ClCCl.CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[O:12])[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indole-5-carboxylic acid (18 mg, 0.11 mmole) and 4-(4-chlorobenzoyl) piperidine hydrochloride (26 mg, 0.1 mmole) were dissolved in 5 ml dichloromethane. To this solution was added triethylamine (1 eq. to neutralize the HCl salt) catalytic DMAP and EDCI (33 mg, 0.11 mmole). The reaction mxture was stirred at room temperature overnight and then worked up by washing sequentially with 1N HCl, saturated sodium bicarbonate, and saturated sodium chloride. The compound was then purified by flash chromatography on silica gel (40:1 CHCl3/MeOH). 1H NMR (300 Mhz, CDCl3) δ 8.45 (s, 1H), 7.88 (d, 2H), 7.72 (s, 1H), 7.45 (d, 2H), 7.38 (d, 1H), 7.24 (s, 2H), 6.58 (s, 1H), 3.42 (m, 1H), 3.11 (m, 2H), 1.83 (m, 4H), 1.60 (m, 2H).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>O1CCCC1.[Pd]>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)cc3)CC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(CC)cc3)CC2)CC1

Procedure:
A solution of 32.6 g of p-(trans-4-(trans-4-propyl-cyclohexyl)-cyclohexyl)-acetophenone in 320 ml of tetrahydrofuran is hydrogenated over 5 g of 5% Pd-on-C at 40° and under normal pressure until the uptake of H2 ceases. The mixture is filtered and the filtrate is evaporated to give trans-1-p-ethylphenyl-4-(trans-4-propylcyclohexyl)-cyclohexane.
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH:4]=[CH2:5])[CH3:3].[CH3:7][Si:8]([SiH:11]([Si:16]([CH3:19])([CH3:18])[CH3:17])[Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9]>N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[CH3:1][C:2]([OH:6])([CH2:4][CH2:5][Si:11]([Si:12]([CH3:15])([CH3:14])[CH3:13])([Si:16]([CH3:19])([CH3:18])[CH3:17])[Si:8]([CH3:7])([CH3:9])[CH3:10])[CH3:3]
Reactant: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Reactant: C=CC(C)(C)O
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CC(C)(O)CC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Temperature: 110 °C
Yield: 75 %

Procedure:
A dried reaction flask equipped for magnetic stirring and fitted with a reflux condenser was flushed with nitrogen and charged with toluene (500 mL). Oxygen was purged from the system by passing a stream of nitrogen through the solvent, 2-methyl-3-buten-2-ol (43.1 g, 500 mmol), tris(trimethylsilyl)silane (25.0 g, 100 mmol), and 1,1′-azobis(cyclohexanecarbonitrile) (1.22 g, 5 mmol) were added to the flask, and the reaction mixture was heated for 20 hours at 110° C. with stirring. The resulting solution was concentrated under reduced pressure, and distillation under vacuum (bp 90-104° C. at 0.10 mm) afforded the title compound (25.1 g, 74%) as a colorless solid. The distilled product was characterized by the following NMR data: 1H NMR (CDCl3) δ 0.14 (s, 27 H), 0.70-0.80 (m, 2 H), 1.17 (s, 6 H), 1.30 (br s, 1 H), 1.45-1.55 (m, 2 H); 13C NMR (CDCl3) δ 1.06 (9 C), 1.24 (1 C), 28.35 (2 C), 42.99 (1 C), 71.64 (1 C); 29Si NMR (CDCl3) δ −80.90 (1 Si), −12.83 (3 Si).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]2[C:7]([O:13]C(C)C)=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1.B(Cl)(Cl)Cl>>[CH3:1][C:2]1[O:6][C:5]2[C:7]([OH:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1
Reactant: COc1cc(C(=O)c2c(C)oc3c(OC(C)C)c(OC)ccc23)cc(OC)c1OC
Agent: ClB(Cl)Cl
Product: COc1cc(C(=O)c2c(C)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Yield: 82.8 %

Procedure:
Note: A similar reaction when scaled-up with 2-methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzo[b]furan (1.25 gm) and boron trichloride solution (1M solution in DCM, 3.1 mL) gave the title compound (930 mg, 83%).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24]>>[F:16][C:17]1[CH:18]=[C:19]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[C:23]([F:24])([F:25])[F:26]
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 83 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide (intermediate A-12) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as light grey solid in 83% yield. MS: 353.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([Sn](CCCC)(CCCC)CCCC)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Br[C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([N+:48]([O-:50])=[O:49])[CH:42]=1>CN(C=O)C.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>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:41]4[CH:47]=[CH:46][C:44]([NH2:45])=[C:43]([N+:48]([O-:50])=[O:49])[CH:42]=4)[N:14]3[S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:18])=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccc(N3CCN(C)CC3)cc2n1S(=O)(=O)c1ccc(C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3ccc(N)c([N+](=O)[O-])c3)cc3ccc(N4CCN(C)CC4)cc32)cc1
Temperature: 100 °C

Procedure:
6-(4-Methyl-piperazin-1-yl)-1-(toluene-4-sulfonyl)-2-tributylstannanyl-1H-indole (crude) (5.0 g, 7.6 mmol) and 4-bromo-2-nitroaniline (2.05 g, 9.5 mmol) in DMF (50 mL) were placed in a RB flask followed by evacuating and flushing with nitrogen. Pd(PPh3)4 (0.22 g, 0.19 mmol) was added and under nitrogen was heated to 100° C., overnight. Analysis after this period indicated that all starting material had been consumed. Workup was by diluting with EtOAc (200 ml) and repeatedly washing with sat NH4Cl (5×50 ml). Crude NMR spectrum was complex, attributed to the product nitrogen atoms being in various oxidation states. The crude was chromatographically purified (16 cm×6 cm silicagel column, gradient eluting with dichloromethane to 10% methanol in dichloromethane), and all related fractions were pooled together (orange thick oil) 3.0 g, was taken directly to the next step without further purification or attempting to assign the chemical shifts.
Reaction SMILES: C([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[N:13][C:14](C)=[N:15][C:16]=32)[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.C(N)=[NH:26]>>[CH:17]12[CH2:19][CH:10]([CH2:9][NH:8][CH2:18]1)[C:11]1[CH:12]=[N:13][C:14]([NH2:26])=[N:15][C:16]2=1
Reactant: Cc1ncc2c(n1)C1CC2CN(Cc2ccccc2)C1
Reactant: N=CN
Solvent: CC(=O)O
Product: Nc1ncc2c(n1)C1CNCC2C1

Procedure:
Following the method described in Example 13, 10-benzyl-4-methyl-3,5,10-triaza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene and formamidine acetate were converted to the title compound in 18% overall yield. APCl MS m/z 177.1 (M+H)+.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[CH3:13][CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=O.Cl>C(O)C>[CH3:13][C:14]12[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[N:11][C:8]1[CH:7]=[CH:6][C:5]([CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]=12
Reactant: CC(C)c1ccc(NN)cc1
Reactant: CC1Cc2ccccc2C1=O
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C1(C)Cc3ccccc3C1=N2

Procedure:
To a solution of 4-isopropylphenylhydrazine hydrochloride, (6.50 g, 0.035 mmol) in absolute ethanol (140 cm3) was added dropwise 2-methyl-1-indanone, (4.6 g, 0.032 mmol) followed by conc. hydrochloric acid (2.5 cm3). The mixture was refluxed for 2 hours and the ethanol evaporated. The residue was portioned between diethyl ether (100 cm3) and water (100 cm3) and the layers separated. The aqueous phase was extracted with diethyl ether (2×30 cm3) and the organic extracts were washed sequentially with saturated sodium bicarbonate solution and brine, and then dried (Na2SO4). Removal of the solvent gave the title compound which was purified by flash chromatography on silica gel eluting with 10% ethyl acetate/60°-80° petrol, to yield a yellow gum; (1.62 g, 25%); 1H NMR (CDCl3) δ: 7.88 (1H, m), 7.55 (1H, d, J=8.1 Hz) 7.41 (3H, m) 7.30 (1H, d, J=1.8 Hz) 7.23 (1H, dd, J=1.8 Hz and 7.1 Hz) 3.10 (1H, d, J=14.7 Hz) 2.98 (1H, septet, J=7.0 Hz) 2.85 (1H, d, J=14.7 Hz) 1.39 (3H, s) 1.30 (6H, d, J=7.0 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH2:12][N:11]([CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]1)=[O:18])[CH2:10][CH2:9]2)=[O:5])C.[OH-].[Li+]>C1COCC1.CO.O>[CH:25]1([N:22]2[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH2:16][N:11]3[CH2:10][CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[CH2:12]3)[CH2:24][CH2:23]2)[CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)CCN(CC(=O)N1CCN(C3CCC3)CC1)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[2-(4-cyclobutyl-piperazin-1-yl)-2-oxo-ethyl]-1,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid ethyl ester (610 mg, 1.58 mmol) in a mixture of THF-MeOH-water (3:1:1, 5 ml) cooled to 0° C. is added lithium hydroxide (76 mg, 3.16 mmol, 2.0 eq.). The mixture is stirred at rt overnight. The organic solvent is evaporated, and the residue is acidified to pH=5 with hydrochloric acid (2.0 N, about 1.58 ml). The resulting aqueous solution is evaporated to dryness, and the residue is extracted with a DCM-EtOH mixture (9:1, 10 ml×4). The combined organic solution is dried over sodium sulfate, and concentrated to give the title compound. MS (+VE) m/z 356.2 (M++1).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.C([Li])(C)(C)C.[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:29][CH3:30])=[C:15]([C:17]([CH3:28])([CH3:27])[CH2:18][C:19](N2CCOCC2)=[O:20])[CH:16]=1>C1COCC1>[CH:1]1([C:19](=[O:20])[CH2:18][C:17]([C:15]2[CH:16]=[C:11]([F:10])[CH:12]=[CH:13][C:14]=2[O:29][CH3:30])([CH3:28])[CH3:27])[CH2:3][CH2:2]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reactant: BrC1CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(=O)C1CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a solution of cyclopropyl bromide (0.120 g) in THF (0.8 mL) cooled to −70° C., a solution of tert-butyl lithium (1.7 M in pentane, 0.8 mL) was added dropwise over 5 minutes, The mixture was stirred at −70° C. for 30 minutes. A solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.29 g) in THF (1 mL) was then added all at once and the mixture was stirred for 30 minutes. The mixture was quenched with EtOH (0.3 mL) and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and evaporated to give the title compound as an oil (0.23 g).
Reaction SMILES: Cl.[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[Cl:13][C:14]1[S:18][C:17]([C:19](O)=[O:20])=[CH:16][CH:15]=1.N>>[ClH:13].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:19]([C:17]3[S:18][C:14]([Cl:13])=[CH:15][CH:16]=3)=[O:20])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 5-chlorothiophene-2-carboxylic acid (Aldrich) according to methods A and C; yield 56 mg, 0.17 mmol (53%): 1H NMR (300 MHz, methanol-d4) δ 1.95 (d, J=14 Hz, 2H), 2.17 (s, 1 H), 2.29 (d, J=14 Hz, 2H), 2.43 (s, 2H), 3.55 (s, 2H), 3.64 (d, J=2 Hz, 4H), 4.34 (s, 1 H), 7.04 (d, J=4 Hz, 1H), 7.69 (d, J=4 Hz, 1H); MS (DCI/NH3) m/z 297, 299 (M+H)+; Anal. C14H17ClN2OS.HCl.0.1H2O: C, H, N.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:12](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:12][O:10][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(C)=O)s1
Yield: 60.3 %

Procedure:
A solution of 5-acetyl-thiophene-2-carboxylic acid (1 g, 5.88 mmol) in DMF (24 mL) is treated with potassium carbonate (813 mg, 5.88 mmol), then iodomethane (0.368 mL, 5.88 mmol), and stirred for 60 h at rt. The reaction mixture is acidified and extracted into ethyl acetate twice. The combined organic layers are washed with brine, dried, filtered, and concentrated, then taken up in ethyl acetate, washed with saturated aqueous potassium carbonate, dried, filtered and concentrated to give 5-acetyl-thiophene-2-carboxylic acid methyl ester (653 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[C:7]([CH2:15][O:16][CH2:17][CH2:18][CH3:19])[C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:21])(=[O:20])[CH2:4][CH2:3]1.[CH3:23][N:24]1[C:28]([OH:29])=[CH:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C.C(OCC)(=O)C.O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[C:7]([CH2:15][O:16][CH2:17][CH2:18][CH3:19])[C:8]([C:12]([C:27]3[CH:26]=[N:25][N:24]([CH3:23])[C:28]=3[OH:29])=[O:13])=[CH:9][CH:10]=2)[S:5](=[O:20])(=[O:21])[CH2:4][CH2:3]1
Reactant: Cn1nccc1O
Reactant: CCCOCc1c(C(=O)O)ccc2c1S(=O)(=O)CCC2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCOCc1c(C(=O)c2cnn(C)c2O)ccc2c1S(=O)(=O)CCC2(C)C

Procedure:
A solution of 0.6 g (1.84 mmol) of 4,4-dimethyl-8-propoxymethyl-1,1-dioxothiochromane-7-carboxylic acid, 0.18 g (1.84 mmol) of 1-methyl-5-hydroxypyrazole and 0.38 g (1.84 mmol) of N,N-dicyclohexylcarbodiimide in 20 ml of acetonitrile was stirred at room temperature for 12 hours. The reaction mixture was subsequently stirred into a mixture of ethyl acetate and 2% strength aqueous sodium carbonate solution, and the precipitate which formed was filtered off with suction. The organic phase of the filtrate was dried and the solvent was distilled off. The resulting residue was dissolved in 5 ml of 1,4-dioxane, 0.51 g (3.7 mmol) of potassium carbonate were added and the mixture was heated under reflux for 4 hours. After cooling, the reaction mixture was taken up in ethyl acetate/water, and the aqueous phase was adjusted to pH 3 using 2N hydrochloric acid and subsequently extracted with ethyl acetate. The extract was dried and the solvent was removed, giving a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13]([CH3:15])[CH3:14])[C:6](O)=O)#[N:2].[NH:16]([C:18](=[S:20])[NH2:19])[NH2:17]>O=P(Cl)(Cl)Cl>[NH2:19][C:18]1[S:20][C:6]([C:5]2[CH:9]=[CH:10][C:11]([CH2:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=2)[C:1]#[N:2])=[N:17][N:16]=1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1C#N
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)Cc1ccc(-c2nnc(N)s2)cc1C#N
Temperature: 90 °C
Yield: 113 %

Procedure:
To a suspension 3-cyano-4-(2-methylpropyl)benzoic acid (D24) (305 mg) in POCl3 (2 mL) was added hydrazinecarbothioamide (211 mg). The reaction mixture was heated at 90° C. for 3 h. The reaction was quenched with ice water. NaOH solid was added until Ph=8-9. The mixture was extracted with EA/THF for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated to afford the 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D25) (438 mg), which was used for the next step without further purification. MS (ES): C13H14N4S requires 258. found 259.1 (M+H+).
Reaction SMILES: Br[CH2:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C)C=O.C(OCC)(=O)C>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3](=[O:13])[CH2:2][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:7][CH:8]=1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)CCc1ccc(Br)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(Br)cc1)Cn1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 1-bromo-4-(4-bromophenyl)-2-butanone (0.5 mmol) and imidazole (102 mg, 1.5 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture was then diluted with ethyl acetate (15 mL), and the solution was washed with water (4×15 mL). The separated organic phase was dried over anhydrous Na2SO4, and then the solvent was removed under reduced pressure to afford a residue that was chromatographed on a silica gel column using ethyl acetate as mobile phase to give 4-(4-bromophenyl)-1-(1H-imidazol-1-yl)-2-butanone as a white solid (111 mg, 76%): mp 79-80° C., Rf=0.50 (ethyl acetate-methanol 4:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.70 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 4.65 (s, 2H), 6.81 (bs, 1H), 7.02 (d, J=7.6 Hz, 2H), 7.09 (s, 1H), 7.37-7.40 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 28.6, 40.9, 55.7, 120.1, 120.4, 130.0, 131.8, 138.0, 139.1, 202.3; HRMS (EI) Calcd. for C13H13BrN2O: 292.0211 (M+). Found: 292.0219.
Reaction SMILES: NCCCN.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]=[N:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24])([O-])=O>CN(C)C=O>[OH:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[N:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]2=[N:6]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: NCCCN
Solvent: CN(C)C=O
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
11.6 g of 1,3-diaminopropane (0.16 mol) and 2.62 g of Cu-II-acetylacetonate are placed into 100 ml of dimethylformamide, and the whole is heated in an inert atmosphere to 100° C. A solution of 10 g of 2-nitro-2'-hydroxy-5'-methyl-azobenzene in 50 ml of dimethylformamide is then added, and after 3 hours the reaction is finished. The conversion to 2-(2'-hydroxy-5'-methylphenyl)-benzotriazole gives a yield of 64%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.NC1N=C(N2CCC3(CN(C(OCC4C=CC=CC=4)=O)[C@H](C(OCC)=O)C3)CC2)C=C(O[C@@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Agent: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Product: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 1m) by using (S)-2-benzyl 3-ethyl 8-(2-amino-6-((S)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate.
Reaction SMILES: C(C1C=C(C=C(C(C)(C)C)C=1)[O-])(C)(C)C.C(C1C=C(C=C(C(C)(C)C)C=1)[O-])(C)(C)C.[CH3:31][SiH:32]([Zr+2:34]([C:49]1[C:57]2[C:56]3[CH:58]=[CH:59][CH:60]=[CH:61][C:55]=3[CH:54]=[CH:53][C:52]=2[CH2:51][C:50]=1[CH3:62])[C:35]1[C:43]2[C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[CH:40]=[CH:39][C:38]=2[CH2:37][C:36]=1[CH3:48])[CH3:33].C([Cl:66])(=O)C>C1(C)C=CC=CC=1>[Cl-:66].[Cl-:66].[CH3:31][SiH:32]([Zr+2:34]([C:49]1[C:57]2[C:56]3[CH:58]=[CH:59][CH:60]=[CH:61][C:55]=3[CH:54]=[CH:53][C:52]=2[CH2:51][C:50]=1[CH3:62])[C:35]1[C:43]2[C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[CH:40]=[CH:39][C:38]=2[CH2:37][C:36]=1[CH3:48])[CH3:33]
Reactant: CC(=O)Cl
Agent: CC1=C([Zr+2](C2=C(C)Cc3ccc4ccccc4c32)[SiH](C)C)c2c(ccc3ccccc23)C1
Agent: CC(C)(C)c1cc([O-])cc(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.4 g of rac-dimethylsilylbis(2-methylbenzo[e]indenyl)zirconium bis(3,5-di-tert-butylphenoxide) (IV) from example 1 were suspended in 35.8 g of toluene in a dry round-bottomed flask which had been flushed with inert gas and was provided with stopcock and magnetic stirrer bar. At room temperature, 7.5 g of a 10% strength by weight solution of acetyl chloride in toluene were quickly added to this suspension via a dropping funnel. The mixture was stirred at room temperature. After 4 hours, the reaction mixture was filtered through a glass filter frit number 3 under inert gas. The filter cake was washed twice with 10 g of heptane and subsequently dried under reduced pressure. This gave 1.7 g of the compound I as a yellowish powder. The 1H-NMR spectrum of the compound indicated the pure rac form.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.P([O-])([O-])([O-])=O.[OH:18][NH3+:19].O[NH3+].O[NH3+]>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:8])[N:19]([OH:18])[C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Reactant: [NH3+]O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: Cc1ccc2c(c1)C(=O)N(O)C2=O

Procedure:
500 mg (3.08 mmol) of 4-methylphthalic anhydride and 243 mg (1.23 mmol) of hydroxylammonium phosphate were mixed and heated with 1 ml of water at a bath temperature of 130° C. for 3 hours. The cooled mixture was digested with 30 ml of water. The precipitate which formed was filtered off with suction and dried at 60° C. under reduced pressure. The yield was 437 mg (80%).