Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[N:17][CH:18]=3)[N:13]([CH2:24][CH3:25])[C:12]2=[O:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN1CCN(CCCCCN)CC1
Reactant: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(S(C)=O)nc21
Product: CCN1C(=O)N(c2cc(OC)cc(OC)c2)Cc2cnc(NCCCCCN3CCN(C)CC3)nc21
Yield: 31 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-1-ethyl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1365 g (0.745 mmol) of 5-(4-methyl-piperazin-1-yl)-pentylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v), to give 0.041 g (31%) of the title compound:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=[O:26]>>[F:20][C:21]([F:31])([F:32])[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1)=[O:26]
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cccc(C(F)(F)F)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 3-(trifluoromethyl)benzoic acid are converted to the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:34][C:33]4[CH:32]=[N:31][N:30]([CH3:35])[C:29]=4[NH:28][C:27]4[CH:36]=[CH:37][CH:38]=[CH:39][C:26]3=4)=[O:24])=[CH:19][C:18]=2[CH3:40])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:40][C:18]1[CH:19]=[C:20]([C:23]([N:25]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:35])[C:29]=3[NH:28][C:27]3[CH:36]=[CH:37][CH:38]=[CH:39][C:26]2=3)=[O:24])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:41]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E47.1 (1.09 g, 1.95 mmol) was dissolved in methanol (20 ml) and 4M HCl/dioxan solution (20 ml) was added. The mixture was stirred for 3 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in methanol (30 ml) and ammonia (5 ml) then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 0.5% 35% ammonia:4.5% methanol:95% dichloro-methane to 1% 35% ammonia:9% methanol:90% dichloro-methane) to yield the title compound (759 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13](F)=[C:14]([CH:34]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:16])=[CH:4][N:3]=1.[CH3:36][O-:37].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([O:37][CH3:36])=[C:14]([CH:34]=2)[C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:16])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Nc1ncc(C#Cc2ccc(F)c(C(=O)Nc3cc(C(F)(F)F)ccc3N3CCCCC3)c2)cn1
Agent: [Na+]
Product: COc1ccc(C#Cc2cnc(N)nc2)cc1C(=O)Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 16 h

Procedure:
A mixture of 5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-fluoro-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.14 g, 0.29 mmol) and NaOMe (0.5 M solution in methanol, 2.0 mL, 1.0 mmol) in a sealed tube was heated to reflux. After 16 h, the reaction was cooled and partitioned between EtOAc and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The material was purified by preparative TLC, eluting with 30% acetone/dichloromethane to give 5-(2-(2-aminopyrimidin-5-yl)ethynyl)-2-methoxy-N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)benzamide as a white solid. MS m/z=496 [M+H]+. Calc'd for C26H24F3N5O2: 495.
Reaction SMILES: CO[CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[F:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:13][C:7]1[C:6]2[O:5][CH:4]=[CH:3][C:11]=2[C:10]([CH3:12])=[CH:9][CH:8]=1
Reactant: COC(COc1cc(C)ccc1F)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccc(F)c2occc12
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 2-(2,2-dimethoxy-ethoxy)-1-fluoro-4-methyl-benzene (48 g) in toluene (50 ml) was added dropwise to a refluxing solution of polyphosphoric acid (100 g) in toluene (350 ml) under nitrogen. The mixture was heated under reflux for 3 h, cooled to room temperature and sodium hydroxide (2N; 800 ml) added. The mixture was extracted with ether (3×300 ml) and the combined organic extracts washed with brine (2×300 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by column chromatography. Eluting with hexane gave the title compound as a pale yellow oil (14.2 g)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:38][C@H:39]([CH2:68][C:69]1[CH:78]=[CH:77][C:76]2[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=2)[CH:70]=1)[C:40]([NH:42][C@@H:43]([C:55]1[N:59]([CH2:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:58]=[N:57][N:56]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)=[O:41]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:38][C@@H:39]([C:40](=[O:41])[NH:42][C@@H:43]([C:55]2[N:59]([CH2:60][CH2:61][C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)[N:58]=[N:57][N:56]=2)[CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)[CH2:68][C:69]2[CH:78]=[CH:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[CH:70]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@H](Cc2ccc3ccccc3c2)C(=O)N[C@H](Cc2ccc3ccccc3c2)c2nnnn2CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
N-tert-butyloxycarbonylpiperidine-4-carboxylic acid (68 mg; 0.296 mmol) was dissolved in methylene chloride (7 ml). HOBT (40 mg; 0.296 mmol) and EDAC (62 mg; 0.326 mmol) were added and the mixture was stirred 15 min at RT. (2R)-2-Amino-3-(2-naphthyl)-N-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethyl)propionamide (152 mg; 0.296 mmol) was added and stirring was continued overnight. Methylene chloride (25 ml) was added. The organic phase was washed with aqueous sodium hydrogencarbonate (25 ml), aqueous sodium hydrogensulfate (10%; 25 ml) and water (25 ml). The organic phase was dried (Magnesium sulfate) and the solvent removed in vacuo to afford 170 mg of 4-((1R)-2-(2-Naphthyl)-1-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethylcarbamoyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butylester.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]=[C:9]=[S:10])=[O:7].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH3:27]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH3:27])[N:15]([CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[S:10])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: O=C(N=C=S)c1ccco1
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Product: Cc1nc(N)c2nc(C)n(CCCNC(=S)NC(=O)c3ccco3)c2c1C

Procedure:
Using the methods of Examples 75-85, 2-furoylisothiocyanate was reacted with 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 387.1608.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-])=O.[H][H]>[Ni].C(O)C>[F:20][C:19]([F:22])([F:21])[C:17]1[CH:16]=[CH:15][C:5]2[O:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[N:1][C:4]=2[CH:18]=1
Reactant: O=Cc1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: FC(F)(F)c1ccc2c(c1)N=Cc1ccccc1O2

Procedure:
A solution of 55 parts of the ether obtained in the preceding paragraph in 800 parts of ethanol is hydrogenated over Raney nickel catalyst at room temperature and atmospheric pressure. When hydrogen uptake ceases the catalyst is removed by filtration and the ethanol solvent is evaporated. The residue is then dissolved in 500 parts by volume of hexane, filtered, and then cooled. There is then obtained yellowish-white crystals which are separated by filtration to give 8-trifluoromethyl-dibenz[b,f][1,4]oxazepine melting at about 86°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:38]=[CH:37][C:21]5[N:22]=[C:23]([NH:25][C:26]([NH:28][CH2:29][CH2:30][N:31]6[CH2:36][CH2:35][O:34][CH2:33][CH2:32]6)=[O:27])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.N>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11]3[N:12]([C:14]([S:17][C:18]4[CH:38]=[CH:37][C:21]5[N:22]=[C:23]([NH:25][C:26]([NH:28][CH2:29][CH2:30][N:31]6[CH2:36][CH2:35][O:34][CH2:33][CH2:32]6)=[O:27])[S:24][C:20]=5[CH:19]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(Sc3nnc4ccc(-c5ccc(F)cc5)nn34)cc2s1
Agent: N
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(NCCN1CCOCC1)Nc1nc2ccc(Sc3nnc4n3N=C(c3ccc(F)cc3)CC4)cc2s1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 22.9 %

Procedure:
A mixture of 209 mg of 1-(6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-(2-morpholin-4-ylethyl)urea and 241 mg of zinc in 7 cm3 of acetic acid is stirred at 20° C. for 1.5 h and then heated at 50° C. for 3.5 h. 241 mg of zinc are again added and the mixture is again left for 1 h at 50° C. After stirring overnight at 20° C., aqueous ammonia is added so that the reaction mixture changes to an alkaline pH. This mixture is extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium bicarbonate and then with brine and is then dried with magnesium sulphate and evaporated to dryness under vacuum. The residue is purified by chromatography on a Merck cartridge of 25 g of silica 15-40 μm by solid deposit, elution being carried out with a 9/1 mixture of dichloromethane/(dichloromethane:38/methanol:17/aqueous ammonia:2). 48 mg of 1-(6-{[6-(4-fluorophenyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-yl)-3-[2-(morpholin-4-yl)ethyl]urea are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]#[N:26])[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=[CH:24][C:25]2[NH:31][N:30]=[N:29][N:26]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/C=C/C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C=CC=Cc2nnn[nH]2)c1

Procedure:
According to the method described for Example 1, (E,E)-5-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile was allowed to react with sodium azide -ammonium chloride to give 5-[4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-1,3-butadien-1-yl]tetrazole. Recrystallization from methanol gave colorless prisms, m.p.201°-202° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Cl:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31].BrBr.ClCl>C(Cl)(Cl)Cl>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Cl:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][C@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1Br
Agent: BrBr
Agent: ClCl
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-chloro-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenol (Example 60) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: [a]25/D=+19.63° (8.805 mg/mL, CHCl3); NMR (DMSO-d 6); δ13.25-13.22 (broad singlet, 1 H), 8.32 (d, J=8 Hz, 1 H,), 8.70 (d, J=8 Hz, 1 H), 7.81-7.79 (ddd, J=8,7, 1 Hz, 1 H), 7.79 (dd, J 10, 2 Hz, 2 H), 7.64 (ddd, J=8,7, 1 Hz, 1 H), 7.58-7.49 (m, 2 H), 7.42-7.32 (m, 4 H, ), 7.29-7.24 (m, 2 H), 6.66 (d, J=8 Hz, 1 H), 5.32 (t, J=6 Hz, 1 H,), 3.41 (d, J=7 Hz, 2 H); MS (-ESI): [(M-H)+], 2 bromine, 1 chlorine isotope pattern, 663 (40%),665 (100%), 667 (60%), 669 (17%); Anal Calc. for C31H19Br2ClO3S: C, 55.84, H, 2.87, N, 0.00. Found: C, 56.95; H, 3.00, N, 0.24.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:12][C:13]([C:15]2([NH:30]C(=O)OC(C)(C)C)[CH2:20][CH2:19][N:18]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:17][CH2:16]2)=[O:14])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:30][C:15]1([C:13]([NH:12][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][OH:11])=[O:14])[CH2:16][CH2:17][N:18]([C:21]2[C:22]3[CH:29]=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
(S)-3-Amino-3-(4-chlorophenyl)propan-1-ol (Intermediate 47) (2.055 g, 11.07 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (4 g, 11.07 mmol) and DIPEA (5.80 ml, 33.20 mmol) in DMA (40 ml). HATU (4.63 g, 12.18 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness and triturated with dioxane (40 ml) to afford (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) as a white solid. (S)-tert-butyl 4-(1-(4-chlorophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 22) (4.82 g, 82%) was suspended in dioxane (40.0 ml) and 4M hydrogen chloride in dioxane (7.69 ml, 221.36 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5M NH3/MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (1.200 g, 25.3%) as a white solid.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][C@H:13]([CH2:15][Cl:16])[C@@H:12]([OH:17])[C@H:11]([OH:18])[CH2:10]1)C1C=CC=CC=1>CCO>[Cl:16][CH2:15][C@H:13]1[CH2:14][NH:9][CH2:10][C@@H:11]([OH:18])[C@@H:12]1[OH:17].[ClH:1]
Reactant: O[C@@H]1[C@@H](CCl)CN(Cc2ccccc2)C[C@H]1O
Agent: Cl
Solvent: CCO
Product: O[C@@H]1[C@@H](CCl)CNC[C@H]1O
Reaction time: 12 h

Procedure:
5N HCl (4.7 mmol, 0.94 mL) was added to (3R,4R,5S)-1-benzyl-5-(chloromethyl)piperidine-3,4-diol (3) (5.1 mmol, 1.3 g) dissolved in EtOH. Solution was evaporated in vacuo and then co-evaporated 2-3× with EtOH. The residue was redissolved in EtOH and combined with Pd(OH)2 (0.27 g), and hydrogenated at 55 psi for 12 hrs. The catalyst was subsequently filtered through dicalite and the filtrate was evaporated to obtain crude (4) as an HCl salt. This was then chromatographed (5-15% MeOH/NH4OH (9:1) in CHCl3) to give 0.4 g of (4) as a white solid with MH+ of 165 and 1H NMR (DMSO-d6) 1.6 (m, 1H), 2.2 (m, 3H), 2.9 (m, 3H), 3.15 (m, 1H), 3.6 (m, 1H), 3.8 (dd, 1H), 4.68 (d, 1H), 4.88 (d, 1H).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[I:14]CI.N(OC(C)(C)C)=O>C(#N)C.CCOCC>[I:14][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: ICI
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOCC
Product: N#Cc1cc(C(F)(F)F)ccc1I
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-(trifluoromethyl)benzonitrile (Intermediate 7, 15.1 g) and diiodomethane (24 mL) in acetonitrile (150 mL) at 35° C. was added t-butyl nitrite (21 mL) dropwise. The reaction was maintained at approximately 35° C. during the addition. The reaction was aged for 30 min and then heated to 60° C. for 30 minutes. The reaction mixture was cooled, diluted with ether and washed twice with water, twice with aqueous sodium bisulfite, water and then brine. The solution was dried over anhydrous MgSO4, filtered through a silica gel plug and then concentrated giving afford a red oil. The product was purified by silica gel chromatography eluting sequentially with hexanes, 3:1 hexanes/CH2Cl2 and 1:1 hexanes/CH2Cl2 to afford 2-iodo-5-(trifluoromethyl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ 8.10 (d, J=8.5 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 7.52 (dd, J=8.5, 1.8 Hz, 1H).
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=O)[NH:4]1)(=[O:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C(OCC)C>[Cl:14][C:5]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1](=[O:3])(=[O:2])[N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2ccccc21
Solvent: CCOCC
Product: O=S1(=O)N=C(Cl)c2ccccc21
Temperature: 25 °C
Yield: 33.7 %

Procedure:
Saccharin (10.0 g, 0.0546 mol) and phosphorus pentachloride (12.6 g, 0.060 mol) were heated at 170° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature and suspended in diethyl ether (200 mL). The precipitate was collected by filtration, thoroughly washed with diethyl ether and dried to yield 3-chloro-1H-1λ6-benzo[d]isothiazole-1,1-dione (3.7 g, 0.0184 mol) as a white solid which was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C:18]([CH3:19])=[C:17]([CH:20]2[S:25][CH2:24][C:23](=[N:26]O)[CH2:22][S:21]2)[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[C:18]([CH3:19])=[C:17]([C@H:20]2[S:25][CH2:24][C@H:23]([NH2:26])[CH2:22][S:21]2)[N:16]=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(C2SCC(=NO)CS2)ncn1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c([C@H]2SC[C@H](N)CS2)ncn1Cc1ccccc1
Temperature: 70 °C

Procedure:
To a suspension of lithium aluminum hydride (2.9 g., 0.076 mole) in dry tetrahydrofuran (120 ml.) under a nitrogen atmosphere is added dropwise a solution of 2-(1-benzyl-5-methyl-4-imidazolyl)-1,3-dithian-5-one oxime (21.3 g., 0.0668 mole) in dry tetrahydrofuran (130 ml.). After heating at 70° C. for one hour, water (40 ml.) is added cautiously and the mixture is filtered hot. The solvent is evaporated and the residue is chased with ethanol to remove traces of water to give a viscous oil (17.0 g.). Careful chromatography on silica gel by gradient elution with 2-6% methanol/chloroform affords 2.2 g. of the trans isomer and 7.3 g. of the cis isomer as viscous semi-solids.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][C:21]#[N:22]>CN(C)C=O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][C:21]#[N:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A mixture of sodium hydride (1.5 g) and 3-(1-piperidinylmethyl)phenol (11.2 g) in dimethylformamide (60 ml) was stirred at room temperature for 5 h. 4-Bromobutannitrile (9.0 g) was added, and stirring was continued for a further 24 h. The mixture was poured onto ice and extracted with ethyl acetate which was washed with water and brine, and distilled to give the title compound as a colourless oil (14.78 g) b.p. 200°, 0.08 mm; tlc system A Rf 0.8.
Reaction SMILES: [Cl:1][C:2]1[C:19]([C:20]#[N:21])=[CH:18][C:5]2[CH2:6][CH:7]([CH2:9]OS(C(F)(F)F)(=O)=O)[O:8][C:4]=2[CH:3]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:1][C:2]1[C:19]([C:20]#[N:21])=[CH:18][C:5]2[CH2:6][CH:7]([CH2:9][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:8][C:4]=2[CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: N#Cc1cc2c(cc1Cl)OC(COS(=O)(=O)C(F)(F)F)C2
Product: N#Cc1cc2c(cc1Cl)OC(CCCc1ccccc1)C2
Yield: 20 %

Procedure:
Following the process described in example 3 (point B), starting from 6-chloro-2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carbonitrile and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 9:1 (20% yield).