Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:7](=[N:8][S:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[OH2:12]>O1CCOCC1.Cl([O-])(=O)(=O)=O.[Ag+]>[OH:12][CH2:2][C:3]1[C:11]2[C:7](=[N:8][S:9][N:10]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1cccc2nsnc12
Reactant: O
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: OCc1cccc2nsnc12
Temperature: 25 °C
Yield: 63 %

Procedure:
A solution of silver perchlorate (4.75 g, 23 mmol) in water (10 mL) was added to a solution of 4-bromomethyl-2,1,3-benzothiadiazole (4.38 g, 19 mmol) in 1,4-dioxane. The mixture was refluxed for 4 hours to afford a light-yellow suspension. After cooling to room temperature, the precipitate was filtered off through a pad of celite and washed with CH2Cl2. The filtrate was washed with water and brine, dried over Na2SO4. Concentration using a rotary evaporator and subsequent column chromatography on silica gel using hexane/ethyl acetate (5:1) as the eluent afforded 4-hydroxymethyl-2,1,3-benzothiadiazole (2.0 g, 63%) as a light-yellow solid. Rf=0.23 (hexane/ethyl acetate=5:1); 1H NMR (200 MHz, CDCl3) δ2.73 (t,J=6.4 Hz, 1H), 5.18 (d,J=6.4 Hz, 2H), 7.58 (m, 2H), 7.94 (m, 1H); HRMS:Calcd. for C7H6N2OS 166.0201, found 166.0219.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]2[C:20](=[O:21])[NH:19][CH:18]=[CH:17][C:11]=2[N:12]=[C:13](SC)[N:14]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:13]1[N:14]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:10]2[C:20](=[O:21])[NH:19][CH:18]=[CH:17][C:11]=2[N:12]=1
Reactant: CSc1nc(Nc2ccccc2C)c2c(=O)[nH]ccc2n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1Nc1nc(NCCCN)nc2cc[nH]c(=O)c12

Procedure:
The compound was prepared from 4-[(2-methylphenyl)amino]-2-(methylthio)pyrido[4,3-d]pyrimidin-5(6H)-one following a procedure (mCPBA/1,1-dimethylethyl (3-aminopropyl)carbamate and TFA) similar to that described for Example 1 (Scheme 2).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].Cl[C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][C:37]([Cl:43])=[CH:38][CH:39]=2)[N:34]=1>>[F:31][C:2]([F:30])([F:1])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][C:37]([Cl:43])=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:6]
Reactant: Clc1ccc2ccc(Cl)nc2c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCN2CCNCC2)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4ccc(Cl)cc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 21 from 9-(4-piperazin-1-yl-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2,7-dichloro-quinoline.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].O.[NH2:15][NH2:16]>C(OCC)(=O)C>[CH3:12][C:11]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=2)[NH:16][N:15]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A solution of 1-(2-hydroxy-5-nitrophenyl)ethanone (0.54 g, 3 mmol) in anhydrous hydrazine (2 ml) was radiated with microwaves while being stirred at 150° C. for 5 min. Water (0.5 ml) was added at 0° C. to terminate the reaction. The reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. Recrystallization of the residue in dichloromethane produced the title compound (Yield 80%).
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)=O.C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C.C([OH:22])C>>[CH3:1][C:2]1[NH:17][C:16](=[O:22])[C:15](=[CH:14][C:4]=1[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[C:18]#[N:19]
Reactant: CC(=O)Cc1ccncc1
Reactant: CCO
Reactant: CCOC=C(C#N)C#N
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccncc1

Procedure:
The process according to claim 1 where 4-pyridinylmethyl methyl ketone and ethoxymethylenemalononitrile are refluxed in ethanol to produce 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:33])[N:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:20]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C(OCC)(=O)C.O1CCCC1>[S:6]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16](=[O:33])[N:17]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:20]=2)=[CH:13][CH:14]=1)(=[O:7])(=[O:8])[NH2:5]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
80 mg of 3-[4-(tert-butylaminosulfonyl)phenyl]-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 3 ml of trifluoroacetic acid, followed by heating under reflux for 1 hour. It was left to cool to room temperature, and then the reaction mixture was diluted with ethyl acetate/tetrahydrofuran, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, and then evaporated. The resulting crude crystals were washed with ethyl acetate, to give 60 mg of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[N:17]=[CH:18][S:19][CH:20]=2)=[CH:10][C:5]=1[O:6][CH2:7][C:8]#[N:9])([CH3:3])[CH3:2].CC(O[CH:26]([N:30]([CH3:32])C)[N:27](C)C)(C)C.Cl.[NH2:34]C1C=CC=CC=1.C(=O)(O)O.NC(N)=N>O.CN1C(=O)CCC1>[CH:1]([C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[N:17]=[CH:18][S:19][CH:20]=2)=[CH:10][C:5]=1[O:6][C:7]1[C:26]([NH2:27])=[N:30][C:32]([NH2:34])=[N:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(OCC#N)cc1-c1cscn1
Reactant: Nc1ccccc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Agent: Cl
Agent: N=C(N)N
Agent: O=C(O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1cscn1
Temperature: 100 °C
Yield: 44.6 %

Procedure:
A mixture of (2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy)-acetonitrile (0.27 g, 0.94 mmol) and Brederick's reagent (0.35 g, 2.01 mmol) was heated at 100° C. for 2 hrs. Excess Brederick's reagent was removed under reduced pressure. The residue was dissolved in anhydrous EtOH (10 ml) and aniline HCl (0.38 g, 2.93 mmol) was added. The reaction mixture was heated at 80° C. for 18 hrs and partitioned between EtOAc and water. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Guanidine carbonate (0.27 g, 1.49 mmol) and NMP (10 ml) were added and heated to 120° C. for 10 hrs. The reaction mixture was poured into water and extracted into EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (3% MeOH in methylene chloride with 0.1% NH4OH) gave 5-(2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenoxy)-pyrimidine-2,4-diamine (0.15 g, 68%) as a solid. (M+H)=358.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([NH2:30])=[CH:25][C:24]=1[F:31])=[O:19])[CH3:16].[O:32]([C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH:42]=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OCC)(=O)C>ClC(Cl)C>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@H:21]1[C:23]1[CH:28]=[C:27]([F:29])[C:26]([NH:30][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:40]=2)=[CH:25][C:24]=1[F:31])=[O:19])[CH3:16]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(F)c(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(F)c(NCc2cccc(Oc3ccccc3)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Sodium triacetoxyborohydride (0.244 g, 1.15 mmol) was added to a solution of enantiomerically enriched-(trans)-ethyl-2-(4-amino-2,5-difluorophenyl)cyclopropanecarboxylate (III-1e) (0.110 g, 0.46 mmol) and 3-phenoxybenzaldehyde (0.091 g, 0.46 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature for one hour. The reaction mixture was partitioned between chlroroform and water. The organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate to give 0.127 g (65% yield) of the title compound as a colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.32 (t, J=8.61Hz, 2H), 7.29 (t, J=7.69 Hz, 2H), 7.10 (t, J=7.14 Hz, 1H), 7.06 (d, J=7.69 Hz, 1H), 6.99 (d, J=7.51 Hz, 2H), 6.90 (dd, J=3.11, 8.06 Hz, 1H), 6.55 (dd, J=6.78, 12.09 Hz, 1H), 6.28 (dd, J=7.51, 11.72 Hz, H), 4.36 (br s, 1H), 4.29 (d, J=5.68 Hz, 2H), 4.15 (q, J=7.14 Hz, 2H), 2.50 (m, 1H), 7.79 (m, 1H), 1.53 (m, 1H), 1.27 (t, J=7.14 Hz, 3H), 1.22 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30]([OH:32])=O)[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:70]=[C:69]([O:71][CH:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH:68]=[CH:67][C:66]=1[NH2:78]>>[CH3:63][O:64][C:65]1[CH:70]=[C:69]([O:71][CH:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH:68]=[CH:67][C:66]=1[NH:78][C:30]([C@@H:20]1[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[C@H:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: COc1cc(OC2CCOCC2)ccc1N
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC2CCOCC2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.2 g, 0.35 mmol), was reacted with diisopropylethylamine (0.22 g, 1.7 mmol), diphenylphosphinic chloride (0.16 g, 0.69 mmol), then reacted with 2-methoxy-4-(tetrahydro-pyran-4-yloxy)-phenylamine prepared in Example 156 (0.1 g, 0.52 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [2-methoxy-4-(tetrahydro-pyran-4-yloxy)-phenyl]amide as a off white solid (Yield 0.08 g, 35%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15]Br>CN(C=O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH3:9])([CH3:8])[CH2:2][O:1][CH2:15][CH2:14][O:13][CH3:12]
Reactant: COCCBr
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCC(C)(C)C(=O)OC
Temperature: 25 °C
Yield: 76 %

Procedure:
To a solution of methyl 3-hydroxy-2,2-dimethyl-propionate (2.72 mL, 21.28 mmol) in 3 mL of DMF is added 60% sodium hydride in mineral oil (1.70 g, 42.56 mmol) in one portion, followed by the addition of 2-bromoethyl methyl ether (4.0 mL, 42.56 mmol). The reaction mixture is stirred at room temperature for 3 hs. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and the product is extracted with DCM twice. The organics are combined and washed with water 4 times then brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound. Yield: 76%; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (6H, s), 3.36 (3H, s), 3.48 (2H, s), 3.48-3.52 (2H, m), 3.54-3.60 (2H, m), 3.67 (3H, s).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C1C(=O)N([Cl:27])C(=O)C1>CN(C=O)C>[Cl:27][C:7]1[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:8]=1[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
To a stirred, ice-cooled solution of 1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole from Example 1.81, Step C (1.0 g, 3.83 mmol) in DMF (10 mL) was added NCS (0.56 g, 4.22 mmol) over a period of 10 minutes. The reaction mixture was warmed to ambient temperature and stirred at 55° C. for 6 h. The reaction mixture was cooled and poured into an ice-water mixture with vigorous stirring to form a white solid, which was filtered and washed with cold water until free of DMF. The solid was dried in vacuo to yield 4-chloro-1-isopropyl-5-(2-methoxy-5-nitro-phenyl)-1H-pyrazole (1.1 g, 97%). LCMS m/z (%)=296 M+H+, (35Cl, 100), 298 (37Cl, 28.5). 1H NMR (400 MHz, CDC3) δ: 8.4 (dd, J1=9.09 Hz, J2=2.78 Hz, 1H), 8.19 (d, J=2.8 Hz), 7.6 (s, 1H), 7.14 (d, J=9.18 Hz, 1H), 4.10 (m, 1H), 3.94 (s, 3H), 1.49 (d, J=6.62 Hz, 3H), 1.36 (d, J=6.62 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(=O)(O)[O-].[Na+].[Br:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][C:14]=1[Cl:22]>C(OCC)C.O>[Cl:22][C:14]1[CH:15]=[C:16]([NH:19][C:20]([N:4]([O:3][CH3:2])[CH3:5])=[O:21])[CH:17]=[CH:18][C:13]=1[CH2:12][Br:11]
Reactant: O=C=Nc1ccc(CBr)c(Cl)c1
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CON(C)C(=O)Nc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A stirred solution of 58.3 grams (0.597 mole) of O,N-dimethylhydroxylamine hydrochloride in 400 ml of diethyl ether was cooled to 0° C. and a slurry of 50.2 grams (0.597 mole) of sodium bicarbonate in 50 ml of water was added. Upon completion of addition the reaction mixture stirred at 0° C. for one hour, then a solution of 147.2 grams (0.597 mole) of 4-bromomethyl-3-chlorophenylisocyanate in 100 ml of diethyl ether was added. During the addition, additional diethyl ether was added to the reaction mixture to promote stirring. Upon completion of addition the reaction mixture was stirred for an additional one hour, then was filtered. The filtrate was dried with magnesium sulfate and refiltered. The filtrate was concentrated under reduced pressure to a solid residue. The solid was triturated with ethanol to remove a yellow color. The solid was collected by filtration to give 51.5 grams of 2-chloro-4-[(N-methoxy-N-methylamino)carbonylamino]phenylmethyl bromide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=CC=CC=2C(O)=O)=[CH:5][CH:4]=1)#C.C1N=CN(C(N2C=NC=C2)=[O:24])C=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C1COCC1>[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:24])=[CH:8][CH:7]=1)#[CH:17]
Reactant: C1COCCN1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To 3.50 g (23.9 mmol) 4-ethynylphenyl benzoic acid in 20 mL THF are added 3.88 g (23.9 mmol) CDI. The mixture is stirred at 60° C. for 30 min and then charged with 2.11 mL (23.9 mmol) morpholine. The complete mixture is stirred under reflux for 5 h and at r.t. for 24 h. The solvent is removed in vacuo and the residue is purified by column chromatography (silica gel, EtOAc 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](/[CH:10]=[CH:11]\[CH3:12])[C:3]=1[C:4]#[N:5]>CCO.[Pd]>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: C/C=C\c1cccc(N)c1C#N
Agent: [Pd]
Solvent: CCO
Product: CCCc1cccc(N)c1C#N
Yield: 95.2 %

Procedure:
(Z)-2-Amino-6-(prop-1-enyl)benzonitrile (Example 131b) (0.45 g, 2.82 mmol) and 10% Pd/C (0.17 g) were stirred in EtOH (15 mL) under a hydrogen atmosphere for 4 h. The catalyst was filtered out, and the organic layer was concentrated under vacuum to give 0.43 g (96%) of 2-amino-6-n-propylbenzonitrile as yellow oil, which was used without further purification. MS 161 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:10]([NH:20][CH:21]2[CH2:23][CH2:22]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][C:34](=[O:35])[N:20]([C@H:10]2[C@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH:21]2[CH2:22][CH2:23]2)=[CH:38][CH:39]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: Clc1ccc([C@@H]2CN(Cc3ccccc3)C[C@H]2NC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc(F)cc1)N(C1CC1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A mixture of 2.27 g (6.94 mmol) rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-amine, 987 mg (7.64 mmol) DIPEA, 8.48 mg (0.07 mmol) DMAP and 1.27 g (7.29 mmol) 4-fluorophenyl chloroformate in 40 mL DCM at 0° C. was stirred at room temperature over night and evaporated to dryness. the residue was purified by column chromatography on silica eluting with a gradient formed from TBME and heptane. The product containing fractions were evaporated to yield 1.64 g (51%) of the title compound as colorless viscous oil. MS m/e: 465.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[N:7]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22])[CH2:6][CH2:5]2>[Pd].CO>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH2:6][N:7]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:8]2=[O:15])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccncc1N1CCc2cc(C)c([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1N)C(=O)N(c1cnccc1C)CC2
Yield: 47.4 %

Procedure:
6-Methyl-2-(4-methylpyridin-3-yl)-7-nitro-3,4-dihydroisoquinolin-1(2H)-one (I-69f: 940 mg, 3.154 mmol) was reacted with 10% Pd—C (200 mg) and methanol (15 mL) to afford 400 mg of the product (36% yield). LCMS: 79.19%, m/z=268.1 (M+1)
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:13]1[CH2:14][C:15](=[O:28])[C:16]=3[C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)(C)(C)C.[ClH:30]>C(Cl)Cl.C(O)C.CCOCC>[ClH:30].[ClH:30].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:13]1[CH2:14][C:15](=[O:28])[C:16]=3[C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2
Reactant: COc1cc2c3c(c1OC)C(=O)CC3N(CCCCNC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: COc1cc2c3c(c1OC)C(=O)CC3N(CCCCN)CC2
Yield: 80 %

Procedure:
[4-(7,8-Dimethoxy-1-oxo-2,2a,4,5-tetrahydro-1H-3-aza-acenaphthylen-3-yl)-butyl]-carbamic acid tert-butyl ester (498 mg, 1.22 mmol) is dissolved in a mixture of CH2Cl2 (10 ml) and ethanol (2 ml) and a solution of 2 N HCl in Et2O is added (6 ml, 12 mmol). A brown precipitate appears, which is collected by filtration (367 mg, 80% yield).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]1[S:8][CH2:7][CH2:6][S:5]1.[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[Cl:9][CH2:10][CH2:11][C:12]([S:1][CH2:2][CH2:3][CH:4]1[S:8][CH2:7][CH2:6][S:5]1)=[O:13]
Reactant: SCCC1SCCS1
Reactant: O=C(Cl)CCCl
Solvent: Cc1ccccc1
Product: O=C(CCCl)SCCC1SCCS1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Into a glass-made, 500-mL reaction vessel equipped with a stirrer, the 2-(2′-mercaptoethyl)-1,3-dithiolane produced in Synthesis Example 2 (100 g, 0.60 mole) was weighed, to which 3-chloropropionic acid chloride (80 g, 0.63 mole) was added dropwise at 40° C. over 15 minutes. After the contents were reacted further under stirring at 40° C. for 8 hours, toluene (200 g) was added to the reaction mixture to dissolve the same. The resulting solution was transferred into a separating funnel, in which the solution was washed three times with a 3 wt. % aqueous solution of sodium hydrogen carbonate (300 g). After the organic layer (toluene solution) was washed with purified water (300 g) until the water layer became neutral, the organic layer was taken out, and toluene was then distilled off under reduced pressure to afford 2-[2-(3-chloropropionylthio)ethyl]-1,3-dithiolane (127 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:13][CH2:14][CH:15]([NH2:18])[CH2:16][F:17]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([S:8]([NH:18][CH:15]([CH2:16][F:17])[CH2:14][F:13])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: NC(CF)CF
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(NC(CF)CF)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
2-Chloropyridine-5-sulfonyl chloride (18 g, 85 mmol) was added to a solution of 1,3-difluoro-2-propylamine hydrochloride (11.2 g, 58.1 mmol) in pyridine (25 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes, diluted with ethyl acetate (200 mL) and washed with 3N aq. HCl (3×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane (2×50 mL) and filtered to provide the title compound as an off-white solid (15.7 g, 70%). 1H NMR (500 MHz, CDCl3): δ 8.79 (1H, d, J=2.4 Hz), 8.17 (1H, dd, J=2.6 Hz, 2.5 Hz), 7.49 (1H, d, J=8.2 Hz), 5.25 (1H br s), 4.58 (2H, m), 4.47 (2H, m), 3.77 (1H, m).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:14][CH3:15])=[N:7]2.[Li]C(C)(C)C.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1.CCCCC>[CH3:13][O:12][C:11]1[C:2]([CH:27]([C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[OH:28])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([S:14][CH3:15])[CH:5]=[CH:4]2
Reactant: COc1ccc2nc(SC)ccc2c1Br
Reactant: COc1ccc(C=O)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(OC)ccc3nc(SC)ccc23)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
A solution of 280 mg (1 mmole) of 5-bromo-6-methoxy-2-methylsulfanyl-quinoline in 4 mL THF was cooled to −78° C. and treated with 1.5 mL of 1.5 M t-BuLi in pentane. After stirring for 1.5 hours, 1.5 eq of p-methoxybenzaldehyde was added and the reaction allowed to warm to room temperature. After partitioning between EtOAc and water the product was purified by chromatography on silica gel (1:3 EtOAc/hexane) to afford (6-methoxy-2-methylsulfanyl-quinolin-5-yl)-(4-methoxy-phenyl)methanol (120 mg, 35%).