Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[O:9][N:8]=[C:7]([C:10]3[N:15]=[C:14]([N:16]([CH3:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=[C:12]([NH2:24])[N:11]=3)[N:6]=2)[CH2:2]1.FC(F)(F)[CH2:27][CH:28]=[O:29].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH2:24][C:12]1[N:13]=[C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[C:10]([C:7]2[N:6]=[C:5]([CH:3]3[CH2:2][N:1]([C:28](=[O:29])[CH3:27])[CH2:4]3)[O:9][N:8]=2)[N:11]=1
Reactant: O=CCC(F)(F)F
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CNC3)n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)N1CC(c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.2 %

Procedure:
6-[5-(Azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine (Intermediate 149, 85 mg, 0.26 mmol), 3,3,3-trifluoropropanal (32 μL, 0.28 mmol) and acetic acid (45 μL, 0.78 mmol) were combined in DCE (5 mL) and stirred for 3 h at room temperature. Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added and the mixture was heated to 70 C for 5 h. The reaction mixture was cooled at room temperature, concentrated under vacuum and purified by preparative HPLC, Method C, to afford the title compound as a white solid (25 mg, 26%).
Reaction SMILES: [N:1]([C@@H:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[K+]>C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C@@H:4]([NH2:1])[CH2:5][CH2:6]2
Reactant: [N-]=[N+]=N[C@H]1CCc2cc(Br)ccc21
Agent: [K+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CCc2cc(Br)ccc21
Yield: 80.6 %

Procedure:
(S)-1-Azido-5-bromo-2,3-dihydro-1H-indene (8.09 g, 34.0 mmol) was dissolved in THF (155 ml), then water (17.2 ml) was added, followed by triphenylphosphine (9.8 g, 37.4 mmol). To this mixture, potassium hydroxide (1.0 N, 34.0 ml, 34.0 mmol) was added drop by drop below 25° C. and stirring continued over night at RT. The reaction mixture was then poured into H2O (150 ml) and extracted with EtOAc (2×100 ml). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to give a crude product (17.34 g), which was purified by flash chromatography (silica gel, 100 g, 0% to 40% MeOH in CH2Cl2) to yield the title compound (5.81 g, 81%) as light yellow oil. MS: 211 (M+, 1Br).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:11]2([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:23]([F:29])[CH:24]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 88 %

Procedure:
In a manner similar to the method described in Example 1d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 65b (1 g, 2.1 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1 g, 88%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+].Cl.[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:21]>CO>[CH2:20]([O:22][C:23](=[O:31])[CH2:24][CH:25]([NH:30][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:26][CH:27]([CH3:28])[CH3:29])[CH3:21]
Reactant: CCOC(=O)CC(N)CC(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CCOC(=O)CC(CC(C)C)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 47 %

Procedure:
4-Fluorobenzaldehyde (0.500 mL, 4.66 mmol), sodium acetate (0.766 g, 9.34 mmol), powdered/activated 4 Å molecular sieves (1.0 g) and sodium cyanoborohydride (0.587 g, 9.34 mmol) were added sequentially to a solution of racemic 3-amino-5-methyl-hexanoic acid ethyl ester hydrochloride (0.979 g, 4.67 mmol) in methanol (25 mL) at 25° C. The mixture was stirred at 25° C. for 22 h, and then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the combined filtrate and washings were partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-80% ethyl acetate in hexanes) to afford rac-3-(4-fluoro-benzylamino)-5-methyl-hexanoic acid ethyl ester (0.616 g, 2.19 mmol, 47%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.88 (3H, d, J=3.8 Hz), 0.90 (3H, d, J=3.4 Hz), 1.26 (3H, t, J=7.0 Hz), 1.43-1.49 (1H, m), 1.66-1.76 (1H, m), 2.48 (2H, d, J=6.3 Hz), 3.04-3.11 (1H, m), 3.76 (1H, d, J=13.6 Hz), 3.80 (1H, d, J=12.2 Hz), 4.10-4.18 (2H, m), 6.97-7.01 (2H, m), 7.29-7.32 (2H, m).
Reaction SMILES: C([O-])(=O)C.[O:5]=[C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH2:18])=[NH2+:17])[N:10]=[C:9]([C:22]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[C:24]([F:30])[CH:23]=2)[CH:8]=[CH:7]1.[CH:31]([CH:33]([CH:39]=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35])=O.O>N1C=CC=CC=1>[O:5]=[C:6]1[N:11]([CH2:12][C:13]2[CH:14]=[C:15]([C:16]3[N:18]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:17]=3)[CH:19]=[CH:20][CH:21]=2)[N:10]=[C:9]([C:22]2[CH:23]=[C:24]([F:30])[C:25]([F:29])=[C:26]([F:28])[CH:27]=2)[CH:8]=[CH:7]1
Reactant: NC(=[NH2+])c1cccc(Cn2nc(-c3cc(F)c(F)c(F)c3)ccc2=O)c1
Reactant: CCOC(=O)C(C=O)C=O
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4.7 g (11.23 mmol) of 3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]benzamidinium acetate are suspended in 40 ml of pyridine, and 2.4 g (16.85 mmol) of ethyl 2-formyl-3-oxopropionate (prepared in accordance with S. H. Berz et al., Journal of Organic Chemistry 1982, 47, 2216) are added, and the mixture is stirred at 80° C. for 4 h. A further 500 mg (3.47 mmol) of ethyl 2-formyl-3-oxopropionate are subsequently added, and the mixture is stirred at 80° C. for 1 h. The reaction mixture is stirred into 400 ml of water, and the precipitate is filtered off with suction, washed a number of times with water and dried in a drying cabinet. Yield: 4.43 g of “A29” (76%), Rt=3.58 min (method B), ESI 467.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18]CC)=[O:17])[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.[OH-].[Li+]>ClCCl.O.O1CCOCC1>[CH:28]1([C:33]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=3)[CH2:11][CH:12]([C:16]([OH:18])=[O:17])[CH2:13]2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)C1CNCC(c2ccc(OC)cc2)C1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.83 g (3.05 mmol) of ethyl 5-(4-methoxyphenyl)piperidine-3-carboxylate hydrochloride was dissolved in 10 ml of dichloromethane, and 0.77 g (7.62 mmol) of triethylamine was added at 0° C. 0.83 g (6.09 mmol) of cyclopentanecarbonyl chloride was then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. 35 ml of dioxane, 17.5 ml of water and 0.29 mg (12.2 mmol) of lithium hydroxide were added to the crude product. The mixture was stirred at RT for 1 h. For work-up, the dioxane was removed under reduced pressure, water was added and the reaction mixture was acidified using aqueous 1 N hydrochloric acid solution. The precipitated solid was filtered off and dried under reduced pressure. Yield: 0.84 g (75% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[ClH:11].C(OCC)C.[NH3:17]>C(O)C>[ClH:11].[OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]([NH2:17])=[NH:8])=[CH:4][CH:3]=1
Reactant: N
Reactant: N#CCc1ccc(O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: N=C(N)Cc1ccc(O)cc1
Reaction time: 72 h

Procedure:
p-Hydroxybenzyl cyanide (5.0 g) was dissolved in absolute ethanol (50 ml) and the solution saturated with dry HCl gas over 4 hours at ambient temperature. After standing at 4° C. for 72 hours, dry diethyl ether (200 ml) and light petroleum (100 ml) were added and white crystals were deposited over 2 hours. The solid was isolated by filtration and reacted immediately with saturated ethanolic ammonia (300 ml) for 3 hours at ambient temperature. The reaction mixture was evaporated to dryness on a steam bath and the residue recrystallised from ethanol. Yield 4.36 g M.P. 248° C. (dec.) N.M.R. δ(Dimethylsulphoxide d6) 9.0-9.8 envelope 5H exchangeable with D2O, amidine H, hydroxyl H. 6.85+7.37 AA'BB' quartet 4H (J: 9 Hz) phenyl H; 3.70 singlet 2H benzyl H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([NH2:18])=[C:13]([CH:17]=2)C(O)=O)[CH:6]=[CH:7][CH:8]=1.C[N:20]1CCC[C:21]1=[O:25].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[NH:18][C:21](=[O:25])[NH:20][C:13]=3[CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCCC1=O
Reactant: COc1cccc(-c2ccc(N)c(C(=O)O)c2)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-(3-methoxyphenyl)-2-aminobenzoic acid (2.0g) in 1,4-dioxane (20 mL) add N-methylpyrolidinone (NMP, 5 mL) and triethylamine (1.4 mL), followed by diphenyl phosphoric azide (DPPA, 2.5 g). After stirring at ambient temperature for 30 minutes, heat the mixture to 100° C. for 2 hours, until gas evolution fully subsided. Cool the mixture to ambient temperature and concentrate in vacuo. Dissolve the residue in MeOH and leave to stand for 18 hours. Filter the precipitate and air dry to obtain 5-(3-methoxyphenyl)benzimidazolidin-2-one as a pale yellow solid.
Reaction SMILES: C(O)(C)C.[ClH:5].CNOC.Br[CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[Cl:5][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24]
Reactant: Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
To a suspension of 50 mol of isopropanol containing N,O-dimethylhydroxylamine hydrochloride (3.97 g, 40.0 mmol) was added dropwise 5.56 ml of triethylamine. After 5 minutes, there was added 2.68 g (10.0 mmol) of N-(3-bromopropyl)phthalimide and the mixture was refluxed for 33 hours. This was cooled to room temperature, then poured into 200 ml of saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was separated and was washed with water and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography on silica gel. Development with 30% hexane-chloroform resulted in elution of 1.03 g of N-(3-chloropropyl)phthalimide and further development with chloroform resulted in 1.21 g (yield: 53%) of white crystals of N-[3-(N-methoxy-N-methylamino)propyl]-phthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([CH3:13])([O-:12])=[O:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.8 %

Procedure:
A mixture of 4-bromobenzaldehyde (16.8 g, 91 mmol), nitromethane (24.6 mL, 455 mmol), ammonium acetate (14 g, 182 mmol), and acetic acid (160 mL) was stirred for 4 hours at 100° C. This mixture was cooled to room temperature and poured into water. The precipitate thus produced was collected, washed with water, and dried under a reduced pressure to obtain the title compound (17.4 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:23][CH3:24])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=2)[CH:5]=[CH:4][N:3]=1.[I-].[NH2:26][N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([O:23][CH3:24])=[C:14]([NH:16][C:17](=[O:22])[C:18]([F:20])([F:21])[F:19])[CH:15]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)[CH:5]=[CH:4][N:3]=1
Reactant: N[n+]1ccccc1
Reactant: COc1ccc(C#Cc2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Agent: [I-]
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Yield: 53.5 %

Procedure:
N-[5-[(2-Chloro-4-pyrimidinyl)ethynyl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.7 g, 4.8 mmol) was subjected to cyclization with N-aminopyridinium iodide (2.1 g, 9.6 mmol) according to the procedure of Example 56, Step E to give the desired product (1.15 g, 53%). 1H NMR (400 MHz, d6-DMSO) δ 10.82 (s, 1H), 8.88 (d, J=6.8 Hz, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.39 (d, J=8.4 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.57 (dd, J=8.6 and 1.8 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.21-7.18 (m, 1H), 7.11 (d, J=5.6 Hz, 1H), 3.90 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13]CC)[C:7]([OH:9])=[O:8])[CH3:2].S(=O)(=O)(O)O.O=[CH:22][C:23]([Cl:26])([Cl:25])[Cl:24].C(O)(=O)C1C=CC=CC=1>O>[OH:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[C:7](=[O:8])[O:9][CH:22]2[C:23]([Cl:26])([Cl:25])[Cl:24]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Agent: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOc1cc2c(cc1O)C(C(Cl)(Cl)Cl)OC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.2 %

Procedure:
To a stirred solution of 16.8 g (80 mmoles) of 3,4-diethoxybenzoic acid in 100 ml. of concentrated sulfuric acid were added dropwise over thirty minutes 16 g (110 mmoles) of chloral. The reaction mixture was stirred at 25° C. for twelve hours. Thin layer chromatographic analysis indicated two components, one of which appeared to be the starting benzoic acid. Six grams of chloral were added to the reaction mixture and stirring was continued for two hours. An additional 10 g of chloral were added and the mixture was stirred for another twelve hours. The reaction mixture was then added to 50 g of ice and 50 g of water, and a solid precipitate formed. The solid product was collected by filtration and then crystallized from ethyl acetate to give 3.3 g of white crystals having a melting point above 260° C. The crystals were dissolved in ethanol and the precipitate which formed was collected, m.p. 143°-144° C. 150 mg. NMR and analysis were consistent for a structure representing 5-hydroxy-6-ethoxy-3-(trichloromethyl)phthalide.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OC1C=CC(C([Cl:20])=O)=CC=1)C.C#N>C1C=CC=CC=1>[ClH:20].[CH3:1][N:2]([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Agent: C#N
Agent: CN(C)Cc1ccccc1
Solvent: c1ccccc1
Product: Cl
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
A solution of 135 g (1 mole) of dimethylbenzylamine in 100 ml of benzene was added dropwise, at -2° C, while cooling, in the course of 30 minutes to a mixture of 184 g (1 mole) of para-ethoxybenzoyl chloride and 54 g (2 moles) of anhydrous hydrocyanic acid in 300 ml of benzene at such a rate that the internal temperature did not rise above -20° C during the addition. When the addition was complete, the mixture was stirred for a further 10 minutes at -20° C and the excess hydrocyanic acid was then distilled, under a waterpump vacuum, into a cooled receiver. Dimethylbenzylamine hydrochloride, which was obtained in a crystalline form, was filtered off from the residual reaction mixture. The filtrate was subjected to fractional vacuum distillation. In this way 152 g (87% of theory) of para-ethoxybenzoyl cyanide with a melting point of 43° C were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15]3)=[O:10])[NH2:8])=[CH:4][CH:3]=1.[CH:35]([C@@H:37]1[CH2:41][C@@H:40]([OH:42])[CH2:39][N:38]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([NH:8][CH2:35][C@@H:37]2[CH2:41][C@@H:40]([OH:42])[CH2:39][N:38]2[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:15]3)=[O:10])=[CH:33][CH:34]=1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
0.24 g of the N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea endo compound, obtained in step 1.5, is dissolved in 3 ml of dichloromethane under N2 in the presence of 0.16 g of tert-butyl (2S,4R)-2-formyl-4-hydroxypyrrolidine-1-carboxylate and of 0.233 g of sodium triacetoxyborohydride. The reaction medium is stirred at ambient temperature for 16 h. After evaporation to dryness, 1 ml of methanol and 4 g of Dowex® 50X2 resin are added. The mixture is stirred for 1 h 30 min. After filtration and washing of the resin with tetrahydrofuran and methanol, the expected compound is released by adding a 1N solution of aqueous ammonia in methanol. The methanol is evaporated off, to give 0.28 g of tert-butyl (2S,4R)-2-({[(1R)-1-(4-chlorobenzyl)-2-(3-{cyclohexyl[(diethylamino)carbonyl]-amino}-8-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]amino}-methyl)-4-hydroxypyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[N:21]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C-:29]#[N:30].[Na+]>C(#N)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.[Cu]I>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[N:21]=[C:22]([C:29]#[N:30])[CH:23]=[CH:24][CH:25]=4)[S:16][C:17]=3[CH3:18])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cccc(Br)n4)sc3C)cn2)cc1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(-c3nc(Nc4cccc(C#N)n4)sc3C)cn2)cc1
Yield: 73.4 %

Procedure:
According to Scheme 4 Step 1: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-yl)-6-bromopyridin-2-amine (0.94 mmol, 430 mg), NaCN (3.54 mmol, 174 mg), Pd(PPh3)4 (0.42 mmol, 487 mg) and CuI (0.18 mmol, 34 mg) in acetonitrile (22 mL) was microwaved at 180° C. for 6 hours under nitrogen. After evaporation of the solvent, the resulting crude product was purified by flash chromatography over silica gel using DCM/MeOH (80:20) as eluent to afford 6-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-methylthiazol-2-ylamino)picolinonitrile (0.69 mmol, 277 mg, 73%).
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:3]([O:1][C:2]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1)[CH2:2][CH2:13][CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCOC1(c2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 72 h
Yield: 41 %

Procedure:
A solution of 1 g (4.0 mmol) of 3-hydroxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 5 ml of DMF is added dropwise to a suspension of 300 mg of 60% NaH in 3 ml of DMF, immersed in a bath at 0° C. 2.5 ml of n-iodobutane are added dropwise. The reaction medium is left to stir at 0° C. for 15 minutes and 72 hours at ambient temperature. The medium is hydrolysed by addition of a saturated solution of ammonium chloride, followed by extraction with ethyl acetate. The organic phase is dried and evaporated to dryness. The crude product obtained is purified on silica in a 7/3 heptane/ethyl acetate mixture. 500 mg in the form of a light yellow oil are obtained with a yield of 41%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6](I)=[CH:5]2.[CH2:23]([CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C(C)C>CN(C=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([N:27]1[CH2:28][CH2:29][O:30][CH:25]([CH2:23][CH3:24])[CH2:26]1)=[CH:5]2
Reactant: CCC1CNCCO1
Reactant: COc1ccc(CNc2nc3ccc(Br)cc3cc2I)cc1
Agent: [Cu]I
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCC1CN(c2cc3cc(Br)ccc3nc2NCc2ccc(OC)cc2)CCO1
Temperature: 125 °C

Procedure:
A mixture of 6-bromo-3-iodo-N-(4-methoxybenzyl)quinolin-2-amine (0.30 g, 0.640 mmol, prepared as in Example 1, Step 1-2), 2-ethylmorpholine (1.105 g, 9.59 mmol), copper(I) iodide (6.09 mg, 0.032 mmol), cesium carbonate (0.417 g, 1.279 mmol), and 2-isobutyrylcyclohexanone (0.021 mL, 0.128 mmol) in DMF (3 mL) was heated at 125° C. for 10 min. Some product was observed but mostly starting material. The mixture was heated again at 125° C. for 10 min more. This process was repeated 3× until the starting material was completely consumed. The reaction was brought to RT, poured into water (20 mL) and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated, and chromatographed on silica gel using gradient 2:1 hexanes/EtOAc to afford a brown oil as 6-bromo-3-(2-ethylmorpholino)-N-(4-methoxybenzyl)quinolin-2-amine.