Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[S:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:30]2[CH2:31][CH2:32][S:27][CH2:28][CH2:29]2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCSCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCSCC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and tetrahydro-2H-thiopyran-4-ol in analogy to Example 9c): MS (ISP): 496.2 and 498.1 (M+H)+, 396.1 and 397.9 ((M-Boc)+H)+ (100%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][N:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=3)[CH2:15][CH2:16]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: c1ccc(CN2CCC3(CCNC3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2CCC3(CCN(Cc4ccccc4)C3)C2)nc1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-benzyl-2,7-diazaspiro[4.4]nonane (1.00 g, 4.68 mmol), methyl 6-chloronicotinate (800 mg, 4.68 mmol) and K2CO3 (700 mg, 5.07 mmol) in 5 mL of DMSO was stirred under microwave irradiation for 20 min at a temperature of 150° C. The mixture was poured into EtOAc and washed with sat'd NaHCO3, dried (Na2SO4), filtered and concentrated, giving methyl 6-(7-benzyl-2,7-diazaspiro[4.4]non-2-yl)nicotinate. A bottle containing a suspension of the benzyl amine and 20% Pd(OH)2/C (600 mg, 0.857 mmol) in 20 mL of EtOH was evacuated and purged with H2 gas three times. Using a Parr shaker apparatus, the suspension was agitated under 50 psi of H2 for 20 h. The pressure was released and the mixture filtered through a pad of Celite and concentrated, giving methyl 6-(2,7-diazaspiro[4.4]non-2-yl)nicotinate: 1H NMR (600 MHz, DMSO-d6) δ 8.59 (d, J=2.1 Hz, 1H), 7.89 (dd, J=9.1, 2.3 Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 6.44 (d, J=8.8 Hz, 1H), 3.74 (s, 3H), 3.13 (br s, 4H), 2.89 (t, J=7.3 Hz, 2H), 2.72 (AB, J=7.6 Hz, 2H), 1.92 (br m, 2H), 1.69 (AB, J=7.3 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)=[CH:4][CH:3]=1.[CH2:23]([OH:26])[C:24]#[CH:25]>N1CCCC1.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>[C:17]1([C:16]2[CH:15]=[N:14][N:12]3[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([C:25]#[C:24][CH2:23][OH:26])=[CH:3][CH:4]=4)[CH:9]=[N:10][C:11]=23)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: OCC#Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1

Procedure:
A deoxygenated mixture of 6-(4-bromophenyl)-3-phenylpyrazolo[1,5-a]pyrimidine (2-2, 3.00 g, 8.57 mmol, 1 equiv), propargyl alcohol (1.50 mL, 25.8 mmol, 3.01 equiv), and tetrakis(triphenylphosphine)palladium (0.500 g, 0.433 mmol, 0.050 equiv) in pyrrolidine (50 mL) was heated at reflux for 2.5 hours. The reaction mixture was concentrated, and the residue was suspended in methanol (50 mL) and filtered to give 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]prop-2-yn-1-ol (2-3) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.56 (d, 1H, J=2.4 Hz), 9.07 (d, 1H, J=2.2 Hz), 8.82 (s, 1H), 8.18 (br d, 2H, J=7.8 Hz), 7.92 (d, 2H, J=8.2 Hz), 7.58 (d, 2H, J=8.2 Hz), 7.46 (t, 2H, J=7.8 Hz), 7.27 (t, 1H, J=7.8 Hz), 5.37 (t, 1H, J=6.0 Hz), 4.35 (d, 2H, J=6.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[O:1]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-hydroxymethylpyridine (19.3 ml), t-butyldimethylsilyl chloride (36.2 g) and imidazole (27.2 g) in dimethylformamide (190 ml) was stirred for two hours at room temperature. Water was added to the reaction mixture and extracted with n-hexane. The organic layer was washed with water, dried over magnesium sulfate and then evaporated. The residue was distilled to give 2-t-butyldimethylsiloxymethylpyridine (42.30 g).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[CH:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29]>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])(=[O:17])=[O:16])[CH2:12][N:11]2[CH:28]=[O:29])=[O:9])[CH2:5][CH2:6]1)#[N:3]
Reactant: O=COc1ccc([N+](=O)[O-])cc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3C(F)(F)F)CN2C=O)CC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K5 was coupled with p-nitrophenyl formate in analogy to experiment L27 to give (2S,4R)-1-formyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 416.2 [M+H]+.
Reaction SMILES: [CH:1]12[O:10][CH:7]([CH2:8][CH2:9]1)[CH:6]1[CH:2]2[C:3](=[O:12])[CH2:4][C:5]1=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:29][C:30]1[C:35]([Pb+3])=[C:34]([CH3:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:29][C:30]1[C:35]([CH:4]2[C:3](=[O:12])[CH:2]3[CH:6]([CH:7]4[O:10][CH:1]3[CH2:9][CH2:8]4)[C:5]2=[O:11])=[C:34]([CH3:37])[CH:33]=[C:32]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:31]=1
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 25 °C

Procedure:
To a mixture of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (166 mg, 1 mmol) and 4-dimethylaminopyridine (610 mg, 5 mmol) under an atmosphere of nitrogen is added dry chloroform (5.6 ml), and the mixture is stirred at room temperature until all the solids are dissolved. To this solution is then added dry toluene (2 ml), and 3,5-dimethylbiphen-4-yllead triacetate (0.5 M solution in dry chloroform, 2.4 ml, 1.2 mmol). The reaction mixture is heated at reflux for 1 hour, then cooled to room temperature, acidified to pH1 with 2N aqueous hydrochloric acid, filtered and extracted with dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(3,5-dimethylbiphen-4-yl)-10-oxa-tricyclo[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:15].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>>[Br:15][CH:12]([CH3:13])[C:11]([C:9]1[S:8][C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:10]=1)=[O:14]
Reactant: CCC(=O)c1cc2cccc(Cl)c2s1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Product: CC(Br)C(=O)c1cc2cccc(Cl)c2s1
Yield: 230.4 %

Procedure:
In a similar manner to Example 18, methylthioglycolate (13 g) was reacted with 3-chloro-2-fluorobenzaldehyde (19.57 g) in dimethylformamide to give methyl 7-chlorobenzo[b]thiophene-2-carboxylate, which was hydrolysed, chlorinated and reacted with N,O-dimethylhydroxylamine hydrochloride to give 7-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide, which was reacted with ethylmagnesium bromide to give 1-(7-chlorobenzo[b]thiophen-2-yl)propan-1-one. This ketone (1.17 g) was reacted with phenyltrimethylammonium tribromide (2.15 g) to give 2-bromo-1-(7-chlorobenzo[b]thiophen-2-yl)propan-1-one (2.32 g) which was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:44][C@H:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([NH2:48])=[O:47])(=[O:43])=[O:42])=[CH:37][CH:36]=1.[CH3:55][O:56][C:57](=[O:66])[C:58]1[CH:63]=[CH:62][C:61]([CH2:64]O)=[CH:60][CH:59]=1>O1CCCC1>[CH3:55][O:56][C:57](=[O:66])[C:58]1[CH:63]=[CH:62][C:61]([CH2:64][N:44]([C@@H:45]([C:46](=[O:47])[NH2:48])[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[S:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)(=[O:42])=[O:43])=[CH:60][CH:59]=1
Reactant: NC(=O)[C@H](NS(=O)(=O)c1ccc(Cl)cc1)c1ccccc1
Reactant: COC(=O)c1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CN([C@@H](C(N)=O)c2ccccc2)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (48 mmg, 0.2 mmol) in 0.7 mL of tetrahydrofuran is added diisopropyl azodicarboxylate (0.04 mL, 0.2 mmol) and the reaction stirred for 30 min. To the reaction is added 0.4 mL of tetrahydrofuran, (R)-2-(4-chloro-benzenesulfonylamino)-2-phenyl-acetamide (32 mg, 0.2 mmol), and methyl-4-hydroxymethylbenzoate (73 mg, 0.2 mmol). The reaction is allowed to warm to room temperature and stirred overnight. The solvent is removed and the resultant residue purified by silica gel chromatography to provide the title compound. C13 NMR (100 MHz, CDCl3) 49.9, 52.3, 64.4, 127.9, 129.0, 129.2, 129.4, 129.5, 130.1, 133.5, 139.7, 142.5, 167.0, 171.0. MS 473.1 m/z (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19]CC)=O)=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O)C.[ClH:22].[NH2:23][C:24]([NH2:26])=[NH:25].C[O-].[Na+]>CN(C)C=O.CO>[ClH:22].[ClH:22].[NH:25]([C:4]([C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([NH:25][C:24]([NH2:26])=[NH:23])=[O:19])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:3])[C:24]([NH2:26])=[NH:23]
Reactant: CCOC(=O)C1=Cc2cccc(C(=O)OCC)c2OCC1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)C1=Cc2cccc(C(=O)NC(=N)N)c2OCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To a mixture of ethyl 2,3-dihydro-9-ethoxycarbonyl-1-benzoxepin-4-carboxylate (0.10 g) and guanidine hydrochloride (0.33 g) in N,N-dimethylformamide (2 ml) was added 28% sodium methoxide in methanol (0.66 ml) at room temperature. After the mixture was stirred at room temperature overnight, it was purified by column chromatography on silica gel using a mixture of chloroform and methanol (30:1 to 4:1). The fractions containing objective compound was collected and evaporated in vacuo. The residue was treated with methanol and 4N hydrogen chloride in 1,4-dioxane, and the solvent was evaporated in vacuo. The residue was triturated with ethanol to give (2,3-dihydro-9-guanidinocarbonyl-1-benzoxepin-4-carbonyl)guanidine dihydrochloride (46 mg).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)=[CH:4][N:3]=1.[F:45][C:46]1[CH:47]=[C:48]([NH2:54])[CH:49]=[N:50][C:51]=1[O:52][CH3:53].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.O>[F:45][C:46]1[CH:47]=[C:48]([NH:54][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH2:34][C:35]3[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=3)=[CH:4][N:3]=2)[CH:49]=[N:50][C:51]=1[O:52][CH3:53]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cc4ccc(S(C)(=O)=O)cc4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.58 h
Yield: 53.3 %

Procedure:
4-(2-Fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (602.4 mg, 0.9816 mmol) and 5-fluoro-6-methoxypyridin-3-amine (159.0 mg, 1.119 mmol) were dissolved in THF (10 mL) and the reaction flask was cooled in an ice water bath. Then, lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 3.0 mL, 3.0 mmol) was added via syringe, and the reaction was stirred under nitrogen for 35 min. Then, the reaction was diluted with water (20 mL) and then extracted with DCM. Brine was added to the biphasic mixture and extraction with DCM was continued. Water and MeOH were also added to the aqueous phase to help break up emulsions. The organic extracts (about 350 mL total) were combined and washed with brine (50 mL). The brine layer was extracted with DCM, and all of the organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted funnel with about 2 inches of silica gel; 100:1 DCM/MeOH) to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (384.7 mg). 1H NMR (CDCl3, 400 MHz) δ 11.82 (br s, 1H), 8.63 (d, J=1.96 Hz, 1H), 8.17 (d, J=2.15 Hz, 1H), 8.00 (d, J=12.32 Hz, 1H), 7.95 (d, J=2.15 Hz, 1H), 7.82 (d, J=8.02 Hz, 2H), 7.37 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.41 Hz, 2H), 7.15 (d, J=8.41 Hz, 2H), 6.90-6.81 (m, 4H), 4.86 (s, 2H), 4.77 (s, 2H), 4.01 (s, 5H), 3.82 (s, 3H), 3.80 (s, 3H), 2.96 (s, 3H), 2.58 (s, 3H). m/z (ESI, pos. ion) 736 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1.[Cu](C#N)[C:19]#[N:20].C(N)CN>CN(C=O)C>[C:19]([C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])=[C:4]([F:17])[CH:3]=1)#[N:20]
Reactant: N#C[Cu]C#N
Reactant: O=C(NC1CCCCC1)c1ccc(Br)cc1F
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)NC2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Heat a mixture of 4-bromo-N-cyclohexyl-2-fluoro-benzamide (1.24 g, 4.13 mmol) and copper cyanide (740 mg, 8.26 mmol) in DMF (20 mL) to reflux for 16 h. Cool the mixture to ambient temperature, add aqueous ethylenediamine and stir for 30 min. Extract the mixture with hexane/EtOAc (1:1), dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (5:1) to give the desired intermediate as a white solid (620 mg, 61%). MS (ES−) m/z: 245 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.OC1C2N=NNC=2C=CC=1.CNC(N=C=NCC)CCNC.C(NC(C)C)(C)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:9])([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: CCN=C=NC(CCNC)NC
Agent: Oc1cccc2[nH]nnc12
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.98 g of meta-nitrobenzoic acid in 50 mL of dichloromethane are successively added under argon, at 0° C., 0.81 mL of pyrrolidine, 0.13 g of hydroxybenzotriazole, 2.3 g of 1,3-dimethylaminopropyl-3-ethyl carbodiimide and 3.43 mL of diisopropylamine. The reaction mixture is then stirred at room temperature for 15 hours and then washed with water. The organic phase is then washed with saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 1.92 g of 1-(3-nitrobenzoyl)pyrrolidine, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.CS(C)=O.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
To 5-chloro-2-fluoro-4-iodopyridine (600 mg, 2.331 mmol) was added DMSO (2.2 ml), trans-4-aminocyclohexanol (1074 mg, 9.32 mmol) and TEA (0.390 ml, 2.80 mmol). The resulting reaction mixture was stirred at 75° C. for 24 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 150 ml of ethyl acetate, washed with saturated sodium bicarbonate (1×), water (1×), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude material. The crude material was purified by silica gel chromatography using a 40 g column eluting from 15%-75% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 750 mg of the title compound as free base, which was used in the next step without further purification. LCMS (m/z): 353.0 (MH+), retention time=0.56 min.
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH3:25][C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([CH3:29])[CH2:27][CH3:28].[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([C:26]([CH3:29])([CH3:25])[CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH:42]=[CH:43][C:44]=1[Cl:45]
Reactant: CCC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(Cl)c(Cl)c1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 96.5 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1,1-dimethylpropyl)-benzaldehyde (87.5 mg, 0.50 mmol), 2-(3,4-dichlorophenyl)-ethylamine (94 mg, 0.50 mmol) and sodium borohydride (28 mg, 0.75 mmol). The desired product (169 mg, 97%) was isolated without further purification as a colorless oil. MS (ISP) 350.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1.CC1CCCO1.O.C([O-])([O-])=O.[Na+].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>>[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[N:7]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: Cc1cc(C)c2c(c1)C(=O)CCCN2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1cc(C)c2c(c1)C(=O)CCCN2C(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 50 h
Yield: 91.9 %

Procedure:
Charge a 22 L flask with an overhead stirrer, thermocouple, 3 L addition funnel, baffle, cooling bath and N2 purge and 7,9-dimethyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one hydrochloride (1,000 g, 4.43 moles). Add 2-methyltetrahydrofuran (6.44 kg, 7.5 L, 74.5 moles) and agitate the off-white slurry. Cool to 5-15° C. Add water 2.5 L, 138.8 moles and Na2CO3 (1.12 kg, 3 moles) to the addition funnel then slowly add to the reaction mixture at a fast drip over about 25 m. Charge a 2 L addition funnel with benzyl chloroformate (91.59 kg, 8.86 moles) add dropwise to the reaction, while maintaining the reaction mixture below about 15° C. Transfer the resulting mixture to a flask equipped with a condenser and heat to 25-25° C. and stir for about 50 h. Cool to about 15° C., add HCl (5 M, until the pH is about 5). Separate the layers. Extract the aqueous layer with methyltetrahydrofuran (4 L); combine the organic layers and wash with water (4 l). Concentrate the organic layer at about 40° C. Add IPA (4 L) and then concentrate to 2 L. Transfer to a 12 L flask equipped with an overhead stirrer, thermocouple, heating mantle condenser, 2 L addition funnel and N2 purge. Heat the flask contents to about 70-80° C. and add heptane (5 L). Slowly cool to RT overnight; seed the mixture if necessary to induce crystallization of the titled compound. Cool and collect the solid; rinse the solid with cold heptane and dry in a vacuum at 50° C. to provide 1,316 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3].C(N(CC)CC)C.[Br:23][CH:24]([CH3:28])[C:25](Br)=[O:26]>C1(C)C=CC=CC=1>[Br:23][CH:24]([CH3:28])[C:25]([O:15][C:2]([CH3:1])([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:3])=[O:26]
Reactant: CCCCCCCCCCCC(C)(C)O
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(C)(C)OC(=O)C(C)Br
Temperature: 57.5 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a stirred solution of 2-methyltridecan-2-ol 73 (5 g, 23.4 mmol) in Toluene (50 mL) was added triethylamine (3.29 mL, 23.4 mmol)) and followed by 2-bromopropionyl bromide 58 (5.11 g, 23.7 mmol) at 5-10° C. The reaction mixture was stirred for 3 hours at 55-60° C.; the reaction was monitored by TLC. The reaction mixture was quenched with saturated sodium bicarbonate solution and stirred for 15 minutes at 25-35° C. The aqueous and organic layers were separated, the organic layer was washed with brine, and the combined organic layers were washed with brine solution. The organic layer was dried over Na2SO4 and concentrated under vacuum to afford crude 74 (5 g, yield: 61.27%) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CC(=O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([F:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[CH:14][C:13]=1[F:25]
Reactant: Oc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)COc1ccc(Cl)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 4-chloro-2-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenol (130 mg, 0.36 mmol, 1.0 eq) and Cs2CO3 (175 mg, 0.54 mmol, 1.5 eq) in 2-butanone (20 mL) was added ethyl 2-bromoacetate (59.7 mg, 0.36 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 h. Water was then added and the aqueous layer extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (80 mg, 50%).