Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].C(O)C.[F:11][C:12]([F:16])([F:15])[S:13]Cl>ClCCl>[F:11][C:12]([F:16])([F:15])[S:13][CH2:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)(C)C
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)CSC(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of 3,3-dimethyl-2-butanone (1.13 mole), ethanol (1.5 g.) and dichloromethane (300 ml) was introduced into a sealed and pressure tested 2-liter vessel under reduced pressure. Trifluoromethanesulfenyl chloride (1.05 mole) was then added to the cooled, evacuated vessel. (Caution: It should be noted that trifluoromethanesulfenyl chloride is a highly hazardous material which must be handled with care to avoid inhalation and contact with the skin.) The vessel was warmed to about 25°C. and then rocked for 21/2 to 3 days. The vessel was vented through a cold gas trap (-78°C.) to trap any unreacted trifluoromethane sulfenyl chloride, and then through a scrubbing system to remove the vented hydrogen chloride gas. Residual liquid was transferred to a flask and distilled to give 1-trifluoromethylthio-3,3-dimethyl-2-butanone, b.p. 65°C./10mmHg.
Reaction SMILES: [CH:1]([C:15]1[NH:19][CH:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>[Pd].C(O)C>[CH2:1]([C:15]1[NH:19][CH:18]=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCC=Cc1cc(C(=O)O)c[nH]1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCc1cc(C(=O)O)c[nH]1
Yield: 81.3 %

Procedure:
An ethanol solution (20 ml) of 3.05 g (10 mmol) of 5-(1-tetradecenyl)pyrrole-3-carboxylic acid prepared in the same manner as in Synthetic Example 7 was subjected to catalytic reduction for 2 hours in the presence of 300 mg of 10% palladium black. After removing the solvent the preduct was crystallized from heptane to obtain 2.50 g (82% yield) of a product identical to the one prepared in Example 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[F:21])([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2cccc(Cl)c2F)CCN(C(=O)OC(C)(C)C)C1
Yield: 76.7 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(3-chloro-2-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (8.05 g, 25.5 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 1.53 g, 38.2 mmol), iodomethane (3.17 mL, 51 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (6.45 g, 77%). MS m/z (rel. intensity, 70 eV) 256 (19), 228 (15), 199 (23), 187 (28), 57 (bp).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[CH3:23])(=[O:15])=[O:14])[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH2:29][C@@H:30]([CH2:39][CH3:40])[C@H:31]([OH:38])[C:32]([NH:34][CH:35]1[CH2:37][CH2:36]1)=[O:33].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:35]1([NH:34][C:32](=[O:33])[C@@H:31]([OH:38])[C@@H:30]([NH:29][C:24]([C@@H:9]2[CH2:10][C@@H:11]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])(=[O:15])=[O:14])[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:26])[CH2:39][CH3:40])[CH2:37][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c(C)c1
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(C)cc2C)CN1C(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S,4R)-1-(tert-butoxycarbonyl)-4-(2,4-dimethylphenylsulfonyl)pyrrolidine-2-carboxylic acid (120 mg, 313 μmol, Eq: 1.00, prepared as described in U.S. Pat. Appl. US20100267722), (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride (99.7 mg, 407 μmol, Eq: 1.3), N,N-diisopropylethylamine (121 mg, 164 μA, 939 μmol, Eq: 3) and HATU (202 mg, 532 μmol, Eq: 1.7) were combined with DMF (2 ml) to give a light brown solution. The reaction was stirred overnight at RT. The crude material was purified by preparative HPLC (column: ymc C18 (120 A), 75×30 mm, acetonitrile/water (+0.1% formic acid)=95%-5% to 5%-95% in 8 min, flow: 25 ml/min). After evaporation of solvents, the title compound was obtained as a light brown foam (64.3 mg, 38.2%, MS (m/e)=538.3 [M+H+]).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:13])CCC>>[Li:13][C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: C#Cc1ccccc1
Product: [Li]C#Cc1ccccc1

Procedure:
Phenylacetylene is reacted with one equivalent of butyllithium at −78° C. to give lithiophenylacetylene. Two equivalents of lithiophenylacetylene are reacted with 1,7-bis(chlorotetrwrnethyldisiloxyl)-m-carborane to give 1,7-bis(phenylacetylenetetramethyldisiloxyl)-m-carborane. This latter material can be used in the hydrosilation reaction as 1,7-bis(ethynyltetramethyldisiloxyl)-m-carborane above.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: COc1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-methoxy-phenyl)-carbamic acid tert-butyl ester (Example J9) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a light yellow solid (258 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:15])N(C)OC)=[CH:6][N:5]2[C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10](=[O:15])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:6][N:5]2[C:16]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Product: Nc1nc2ccc(C(=O)c3ccc(F)cc3)cn2c1-c1ccccc1

Procedure:
The 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (584 mg, 1.97 mmol) and 1-bromo-4-fluorobenzene were converted to product in a manner substantially analogous to Example 141 to yield 205 mg. (52%). NMR (200 MHz, CDCl3) d 4.31 (bs, 2H, NH), 7.15 (m, 2H, F—ArH ), 7.25-7.56 (m, 7H, ArH+H7+H8), 7.78 (m, 2H, F—ArH), 8.69 (s, H5).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[S:18])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1cc(C)c(C)cc1NC(=S)Oc1ccccc1
Product: COc1cc(C)c(C)cc1NC(=S)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 85 %

Procedure:
Phenyl N-(4,5-dimethyl-2-methoxyphenyl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[N:10]=3)[CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC1(C)C(=O)N=C2C=CC(Br)=CN21
Product: COc1cccc(C2=CN3C(=NC(=O)C3(C)C)C=C2)c1
Yield: 54 %

Procedure:
The title compound was prepared in 54% yield according to the procedure described in Example 2, starting from 6-bromo-3,3-dimethyl-imidazo[1,2-a]pyridin-2-one and 3-methoxyphenyl boronic acid. 1H NMR (CDCl3) δ7.86 (dd, J=2.1 and 9.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.43-7.39 (m, 1H), 7.28-7.25 (m, 1H), 7.05 (m, 1H), 6.97-6.94 (m, 2H), 3.88 (s, 3H), 1.63 (s, 6H); MS (m/e): 269 (MH+).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C:22]([CH3:26])([CH3:25])[CH2:23]O>>[CH3:23][C:22]1([CH3:26])[CH2:25][O:20][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:21]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(N)CO
Product: CCCCCCCCCCCCCCCCCC1=NC(C)(C)CO1
Yield: 79.7 %

Procedure:
Following example 8, 14.9 g (52.4 mmoles) of octadecanoic acid and 9.34 g (104.8 mmoles) of 2-amino-2-methylpropanol gave 14.1 g (79.7%) of product, b.p. 140°-143° C./0.01 mm Hg.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 19 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.044 g, 0.11 mmol) and EtOH (3.5 ml) was added 4-morpholin-4-ylmethyl-benzaldehyde (0.029 g, 0.14 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was stirred at 80° C. for 19 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with ethyl acetate/dichloromethane (v:v; 2:3) and then a gradient of methanol (2 to 8%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.012 g, 20%); 1H-NMR (500 MHz, DMSO-d6) 2.38 (br s, 4H) and 3.59 (t, J=4.6 Hz, 4H) (morpholine N(CH2)2 and morpholine O(CH2)2), 2.40 (s, 3H, isoxazole 5-CH3), 2.64 (br s, 4H, piperazine N(CH2)2), 3.54 (s, 2H) and 3.60 (s, 2H) (C6H4CH2N and NCH2 isoxazole), 3.67 (br s, 4H, piperazine N(CH2)2), 6.25 (s, 1H, isoxazole 4-H), 7.48 (d, J=8.2 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.[CH2:23]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>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.O>[CH3:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:31][CH:32]=1
Reactant: Cc1ccc(C)c(Br)c1
Reactant: CCCCCCOc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc(-c2cc(C)ccc2C)cc1
Temperature: 85 °C
Reaction time: 20 h

Procedure:
Bromo-p-xylene (8.3 g, 45 mmol) (cf. A1 a)), K2CO3 (12.4 g, 90 mmol), 70 ml of toluene and 70 ml of H2O were placed in a reaction vessel and argon was passed in for 30 minutes. 4-hexyloxyphenylboronic acid (10 g, 45 mmol) and Pd(PPh3)4 (0.65 g, 0.56 mmol) were subsequently added under protective gas. The yellow-green, turbid mixture was stirred vigorously under a blanket of protective gas for about 20 hours at an internal temperature of 85° C. After phase separation, the organic phase was shaken with dilute HCl/H2O (until neutral). The aqueous phase was shaken with toluene and the organic phases were combined. After filtering off any palladium residues, the solution was evaporated. The crude product was purified by distillation under reduced pressure: the product was obtained as a yellow oil (boiling point: 117°-125° C./0.08 mbar): 10.3 g (81%). Purity >95% (1H-NMR).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]2[C:12]=1[NH:11][C:10]([CH3:13])=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.[C:25]([O:29][C:30](=[O:33])[CH2:31]Br)([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[CH3:26][C:25]([O:29][C:30](=[O:33])[CH2:31][N:11]1[C:12]2[C:8](=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=[CH:5][C:4]=2[Br:3])[C:9]([O:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[C:10]1[CH3:13])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]c2c(Br)ccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(Cl)cc2)c2c([N+](=O)[O-])ccc(Br)c2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% disp. in oil) (0.043 g) was added to a stirred solution of the product from step (ii) (0.34 g) in THF (4 ml) at RT. After 1 h, tert-butylbromoacetate (170 ul) was added, the mixture stirred at RT for 16 h then quenched with water and extracted with diethylether. The organics were dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% diethylether/iso-hexane. Yield 0.192 g
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]12([NH2:15])[CH2:14][CH:12]([CH2:13]1)[CH2:11]2>C(#N)C>[C:10]12([NH:15][C:3]3[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=3)[CH2:14][CH:12]([CH2:13]1)[CH2:11]2
Reactant: NC12CC(C1)C2
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CC#N
Product: Clc1ncc(Br)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 5-Bromo-2,4-dichloro-pyrimidine (6 g, 26.3 mmol) and bicyclo[1.1.1]pent-1-ylamine (4.7 g, 39.5 mmol) in acetonitrile (60 mL), was added TEA (16.5 mL, 118 mmol), and the mixture was stirred at 25° C. for 18 hours. The volatiles were removed in vacuo and the residue partitioned between water and EtOAc. The organic phase was dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc:Hexane 1:99) afforded the title compound as a white solid in 82% yield, 4.8 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:11]1[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine in CH3CN with 2-Bromomethyl-5-cyano-benzoic acid methyl ester, DIPEA and KI gave 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8yl)amino]-methyl}-benzoic acid methyl ester as a red oil. 1H NMR (CDCl3) δ 1.76 (m, 1H), 2.06 (m, 2H), 2.16 (s, 3H), 2.27 (s, 3H), 2.28 (m, 1H), 2.75 (m, 2H), 3.86 (m, 2H), 3.90 (s, 3H), 4.15 (m, 1H), 4.29 (m, 2H), 6.99 (d, 2H, J=15.8 Hz), 7.35 (d, 1H, J=6.6 Hz), 7.46 (d, 1H, J=7.9 Hz), 7.88 (s, 1H), 8.01 (s, 2H), 8.51 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([F:18])=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl-].[NH4+]>CCO.[Zn]>[CH2:1]([O:8][C:9]1[C:10]([F:19])=[CH:11][C:12]([F:18])=[CH:13][C:14]=1[NH2:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)cc(F)c1OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 2-benzyloxy-1,5-difluoro-3-nitrobenzene (2.60 g, 9.80 mmol) in EtOH (20 mL)/water (10 mL) is added zinc (3.4 g, 49 mmol) and ammonium chloride (1.0 g, 19.6 mmol) and the mixture is heated at 60° C. for 2 h. The mixture is extracted with EtOAc and the solvent is removed under reduced pressure. The residue is dissolved in methylene chloride and the solution washed with water. The organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound which is used directly to the next step without purification.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si:19]([O:26][CH2:27][CH:28]1[O:33][CH2:32][CH2:31][NH:30][CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:19]([O:26][CH2:27][CH:28]1[CH2:29][N:30]([C:2]2[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=2)[CH2:31][CH2:32][O:33]1)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCCO1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCOC(CO[Si](C)(C)C(C)(C)C)C2)c1Cl
Temperature: 100 °C
Yield: 42 %

Procedure:
A round bottom flask was charged with tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (2.020 g, 6.09 mmol), (+/−)-2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine (1.692 g, 7.31 mmol), Pd2(dba)3 (0.558 g, 0.609 mmol) and BINAP (0.379 g, 0.609 mmol) in toluene (20.31 ml). The flask was evacuated and purged with nitrogen (4×) and heated at 100° C. 8 h and cooled to room temperature ON. The reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on the ISCO system (80 g, 0-100% EtOAc/CH2Cl2) to provide (+/−)-tert-butyl (3-(2-(((tert-butyldimethylsilyl)oxy)methyl)morpholino)-2-chloro-5-cyanophenyl)carbamate (1.2321 g) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29](O)=[O:30])[CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1.[NH2:32][O:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][O:35]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]3([CH2:25][C:24](=[O:26])[C:23]4[C:18](=[CH:19][CH:20]=[C:21](/[CH:27]=[CH:28]/[C:29]([NH:32][O:33][CH:34]5[CH2:39][CH2:38][CH2:37][CH2:36][O:35]5)=[O:30])[CH:22]=4)[O:17]3)[CH2:13][CH2:12]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)c1
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: COc1cccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)c1

Procedure:
(E)-3-{1′-[2-(3-Methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (165 mg, 0.360 mmol) was suspended in DCM (5 ml). TEA (0.075 ml, 0.54 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(3-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a yellow solid. The compound was then dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving a light yellow solid (103 mg, hydrochloride salt).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[H-].[Li+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: O=C(O)COCCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Li+]
Product: OCCOCCc1ccc(Cl)cc1
Yield: 43 %

Procedure:
The 2-(4-chlorophenyl)ethoxyacetic acid obtained according to the preceding paragraph was reduced with lithium hydride in a manner analogous to that described in Example 1(b) to give 1.6 g (43%) of 2-[2-(4-chlorophenyl)-ethoxy]ethanol in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]([CH2:46][CH2:47][O:48][CH2:49][CH3:50])[CH3:45])=O>>[CH2:8]([O:10][CH2:41][CH2:42][N:44]([CH3:45])[CH2:46][CH2:47][O:48][C:49]1[CH:50]=[CH:6][C:5]([CH2:14][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:4][CH:9]=1)[CH3:7]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCOCCN(C)C(=O)CCl
Product: CCOCCN(C)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 27.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N-(2-ethoxyethyl)-N-methylacetamide (9.8 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.3 mg) was obtained.