Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[C:3]=1[C:4]#[N:5].B.[H][H].Cl>C1COCC1.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[C:3]=1[CH2:4][NH2:5]
Reactant: [H][H]
Reactant: CCOc1cccc(Cl)c1C#N
Agent: B
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cccc(Cl)c1CN
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 2-chloro-6-ethoxybenzonitrile, 135, (93.2 g, 0.513 mol) in THF (350 mL) at room temperature under a dry nitrogen atmosphere was added borane in THF (1.0 M, 620 mL, 0.62 mol). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. Water (250 mL) was added very slowly to the solution allowing for the evolution of hydrogen. Concentrated HCl (50 mL) was then added over several minutes and the solution was heated to 50° C. for 2 hours. The mixture was cooled and partitioned between chloroform and water. The aqueous layer was washed 6 times with chloroform. The combined organic fractions were washed with HCl (1 M) and this organic layer was discarded. Chloroform was added to the combined aqueous layers and solid KOH was added until the aqueous phase was basic (pH>9). The aqueous layer washed with chloroform an additional five times. The organic fractions were combined and washed with water, brine, and dried over MgSO4 and silica gel (2 g). This mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-chloro-6-ethoxybenzylamine, 136, (60.1 g, 64% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([OH:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.[Cl-].[NH4+].C1C=CC2N(O)N=[N:32]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:32])=[O:23])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(=O)O)s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Yield: 90.5 %

Procedure:
A mixture of 2-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxylic acid (1.70 g, 5.0 mmol) obtained in Example 35-B(viii), TEA (2.1 mL), ammonium chloride (803 mg, 15.0 mmol), HOBT (1.01 g, 7.5 mmol), EDCI (1.44 g, 7.5 mmol) and DMF (50 mL) was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. To the residue was added saturated aqueous solution of sodium bicarbonate (30 mL). The resulting precipitate was collected by filtration and was washed with water and diethyl ether to give the title compound (1.54 g, 90%) as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH3:29])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:39][C:40]([Cl:45])([Cl:44])[C:41](Cl)=[O:42]>ClCCl>[Cl:39][C:40]([Cl:45])([Cl:44])[C:41]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH3:29])=[CH:21][CH:22]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:42]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)C(Cl)(Cl)Cl)n4Cc4ccccc43)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.7 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(2-methyl-cyclohex-1-en-1-yl)-phenyl]-methanone of Step D (1 g, 2.21 mmol) and N,N-diisopropylethylamine (0.770 mL, 4.42 mmol) were combined in anhydrous dichloromethane (11.1 mL) and trichloroacetyl chloride (0.740 mL, 6.63 mmol) was added dropwise. After stirring at room temperature for four hours, the solvent was removed and the residue dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue purified by flash column chromatography. Recrystallization from petroleum ether afforded 1.21 g of the title compound as white crystals, m.p. 171° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(NC(C)C)(C)C.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36]>O.[Cu]I.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>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:38]#[C:37][C:35]([OH:39])([CH3:36])[CH3:34])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2

Procedure:
A 25-mL flask was charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (1.012 g, 2.91 mmol), copper(i) iodide (0.055 g, 0.291 mmol), and tetrakis(triphenylphosphine)palladium (0.034 g, 0.029 mmol). The vial was flushed with Ar(g), then a septum was attached. DMF (5.81 mL), diisopropylamine (6.11 mL, 43.6 mmol), and 2-methylbut-3-yn-2-ol (1.137 mL, 11.63 mmol) were added in sequence to give a clear, brown solution. A reflux condenser was attached, and the flask was placed in a 75° C. oil bath for 4 hours. The mixture was diluted with water (35 mL) and extracted with DCM (4×20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue, which contained a considerable amount of DMF, was loaded onto a 10-g SCX-2 column with the aid of methanol. The column was eluted with methanol to remove impurities, then with 2M ammonia in methanol to elute the product. The filtrate was evaporated, and the residue was chromatographed on an 80-g Redi-Sep column, eluting with 0-10% MeOH/DCM to give (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[C:10]([CH2:16][CH3:17])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:18]1[CH2:23][CH2:22][CH:21]([N:24]2[CH2:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][C:25]2=[O:35])[CH2:20][CH2:19]1.C1C[O:39][CH2:38]C1>>[CH2:16]([C:10]1[CH:9]=[C:8]([CH2:7][CH:2]([NH:1][C:38]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:30][CH2:29][C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[NH:26][C:25]3=[O:35])[CH2:22][CH2:23]2)=[O:39])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:15])[CH3:17]
Reactant: C1CCOC1
Reactant: CCc1ccc(CC(N)C(=O)OC)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.4 g (45 mmol) of CDT were added to a solution of 10.5 g (44.6 mmol) of methyl 2-amino-3-(3,4-diethyl-phenyl)-propionate in 250 mL of THF cooled to 0° C. and stirred for a further 30 min at this temperature. Then 10.9 g (44.6 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one was added and the reaction solution was kept for a further 20 min at this temperature before being refluxed for 30 min. The solvent was removed in vacuo, the residue was taken up in saturated NaHCO3 solution, exhaustively extracted with diethyl ether/EtOAc (1:1) and dried over MgSO4. After elimination of the desiccant and solvent the crude product was reacted without any further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1C2C(=CC(C3C=CC=CC=3)=CC=2)N=C(N2C=C(C(O)=O)C=N2)N1.[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1B(O)O>>[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:27])[NH:20][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)=[N:12]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Reactant: OB(O)c1ccccc1Cl
Agent: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4Cl)ccc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 2-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 13.02 (br s, 1H), 12.92 (br s, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 8.22 (d, J=6.6 Hz, 1H), 7.71 (s, 1H), 7.67-7.62 (m, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.55-7.47 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:15]1([N:21]=[C:22]=[N:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CN(C=O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:22]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: c1ccc(CN2CCC(NC(=NC3CCCCC3)NC3CCCCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
3.8 g of 4-amino-1-benzylpiperidine (20 mmol) was combined with 4.7 g of dicyclohexylcarbodiimide (23 mmol) in 80 ml of DMF and stirred for 12 hours at 80° C. The solvent was evaporated in vacuo and the residue was flash chromatographed using ethyl acetate/methanol (1:1) whereby 54. g of 1-benzyl-4(N′, N″-dicyclohexyl-guanidino)-piperidine was obtained (71%). 5 g of the product (12.6 mmol) was dissolved in 60 ml of methanol and hydrogenated using 0.6 g of Pd(C) at 2 bar hydrogen pressure. Thus obtained was 4 g of 4(N′, N″-dicyclohexyl-guanidino)-piperidine (63%)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH2:29][CH3:30])([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([OH:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([CH3:28])[CH:15]=2)[CH2:12][CH3:13])=[CH:8][C:9]=1[CH3:10])=[O:4].N1C=CN=C1.CN(C=O)C.[CH3:41][C:42]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CCOCC>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([O:27][Si:45]([C:42]([CH3:44])([CH3:43])[CH3:41])([CH3:47])[CH3:46])[C:23]([CH3:24])([CH3:25])[CH3:26])=[C:16]([CH3:28])[CH:15]=2)([CH2:12][CH3:13])[CH2:29][CH3:30])=[CH:8][C:9]=1[CH3:10])=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(C(=O)OC)s1
Reaction time: 24 h
Yield: 64.6 %

Procedure:
To a mixture of 5-{1-Ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-3-methyl-thiophene-2-carboxylic acid methyl ester (Example 2) (1.15 g, 2.66 mmol), imidazole (0.27 g, 4.00 mmol), and DMF (15 mL) is added TBSCl (0.54 g, 2.80 mmol). The reaction is stirred for 24 h. The reaction is diluted with Et2O (120 mL) and washed with 0.1 M HCl (3×40 ml). The organic layer is MgSO4 dried and concentrated. The resulting residue is chromatographed to give the title compound (0.94 g, 64%). 1H NMR (CDCl3), δ 0.01 (s, 3H), 0.06 (s, 3H), 0.65 (t, J=7.4 Hz, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 2.00-2.14 (m, 4H), 2.14 (s, 3H), 2.43 (s, 3H), 3.67 (dd, J=5.8, 3.4 Hz, 1H), 3.74 (s, 3H), 3.85 (dd, J=9.8, 5.8 Hz, 1H), 3.98 (dd, J=9.8, 3.4 Hz, 1H), 6.56 (s, 1H), 6.68 (d, J=8.3 Hz, 1H), 6.96-7.03 (m, 2H). LC/MS (m/z): calcd for C31H51O4SSi (M+H)+: 547.9; found: 547.2.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:16]([I:18])[CH3:17].[CH3:19]COCC>C(#N)C>[I-:18].[CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][N+:12]([CH2:19][CH2:16][CH3:17])=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(-c2ccncc2)cc1
Reactant: CCI
Reactant: CCOCC
Solvent: CC#N
Product: CCC[n+]1ccc(-c2ccc(N(C)C)cc2)cc1
Product: [I-]
Temperature: 25 °C
Yield: 29 %

Procedure:
IDT322. Was prepared by refluxing N,N-dimethyl-4-(pyridine-4-yl) aniline (II) in acetonitrile in the presence of ethyl iodide. After which the solution was cooled to room temperature. Ether was added and the product crystallized resulting in a 29% of 4-(4-(dimethylamino)phenyl)-1-propylpyridinium iodide (IDT322) (V).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>C(OCC)C.Cl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[C:6]2[CH3:18]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(-c2cccnc2)n(COC(=O)C(C)(C)C)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 5-chloro-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 2, 1.0 g, 3.58 mmol) and THF (20 mL) and cooled to 0° C. KHMDS (0.5 M in toluene, 17.9 mL, 8.95 mmol) is added and the mixture is stirred at room temperature for 30 min, followed by addition of 2,2-dimethyl-propionic acid chloromethyl ester (2.58 mL, 8.95 mmol). The reaction mixture is stirred at room temperature for 3.5 h, then washed with water and extracted with ethyl acetate twice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (heptane-ethyl acetate, 1:1) to afford an oil, which is taken up in diethyl ether. A few drops of concentrated HCl are added. Evaporation of the solvent and lyophilization give 2,2-dimethyl-propionic acid 5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl ester as a solid. 1H NMR (400 MHz, MeOD) δ ppm (HCl salt) 1.12 (s, 9H), 2.27 (s, 3H), 6.06 (s, 2H), 7.30 (dd, J=8.6, 2.0 Hz, 1H), 7.60 (s, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.74 (dd, J=7.8, 5.1 Hz, 1H), 8.01-8.16 (m, 1H), 8.64-8.79 (m, 2H). HRMS (ESI) m/z 357.1121 [(M+H)+ Calcd for C20H22ClN2O2: 357.1127].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[S:10])=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19]([OH:21])=[O:20].C1C=CC=CC=1>CCOCC>[Br-:17].[C:19]([CH2:18][S:10][C:9](=[N+:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([OH:21])=[O:20]
Reactant: S=C(Cc1ccc(Cl)cc1)N1CCCCC1
Reactant: O=C(O)CBr
Solvent: CCOCC
Solvent: c1ccccc1
Product: O=C(O)CSC(Cc1ccc(Cl)cc1)=[N+]1CCCCC1
Product: [Br-]
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A mixture of 200 g of N-(4-chlorophenylthioacetyl)piperidine, 117.5 g of bromoacetic acid and 600 ml of benzene was stirred overnight, then diluted with anhydrous ether and stirred overnight. The solid was collected and dried in vacuo giving 241 g of 1-[1-[(carboxymethyl)thio]-2-(4-chlorophenyl)ethylidene]piperidinium bromide, mp 118-120° C.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH2:4][CH2:3][C:2]1=[O:11].[BH3-]C#N.[Na+].Cl>O1CCOCC1.CCOC(C)=O>[NH:1]1[C@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCC2=C(CCCC2)N1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C1CC[C@@H]2CCCC[C@H]2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3,4,5,6,7,8-hexahydro-1H-quinoline-2-one (0.1 g, 0.66 mmol) in dioxane (10 mL) containing a catalytic quantity (40 μL) was added NaCNBH3 (0.67 g). The reduction was left to stir for 20 hrs at r.t., and then diluted with EtOAc. The organic phase was treated with dilute HCl (3×), and the combined organics were washed with saturated HCO3−, brine, dried over Na2SO4, filtered and concentrated to afford the mainly traits product (98 mg, 95%, 15-20% cis isomer). MS (+ES) m/z 254 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH3:12])[CH:3]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CO.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:39]([CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1)[CH2:12]2
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccc(Br)cc2CN1Cc1ccc(F)cc1
Yield: 34.2 %

Procedure:
A mixture of 458 mg methyl 4-bromo-2-methylbenzoate, 427 mg N-bromosuccinimide, 25 mg α,α′-azobisisobutyronitrile and 10 mL carbon tetrachloride was heated for 30 minutes under reflux. 50 mg N-bromosuccinimide was added thereto, and the mixture was further heated for 30 minutes under reflux. The reaction solution was cooled, insolubles were filtered off, and the filtrate was evaporated. 773 mg crude product of methyl 4-bromo-2-bromomethyl benzoate was obtained as a pale yellow oil. A mixture of this compound, 546 mg 4-fluorobenzyl amine, 0.34 mL triethylamine and 10 mL methanol was heated for 2 days under reflux. The reaction solution was cooled, and the precipitated crystals were collected by filtration and dried under reduced pressure with a vacuum pump, to give 219 mg of the title compound as pale brown crystals.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25](S(C)=O)[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C@H:37]([CH2:39][OH:40])[CH3:38]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:32](=[O:33])[N:31]([CH3:34])[C:23]4[N:24]=[C:25]([NH:36][C@@H:37]([CH3:38])[CH2:39][OH:40])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)CO
Reactant: Cn1c(=O)c(-c2ccc(F)c(NC(=O)Nc3cc(C(C)(C)C)no3)c2)cc2cnc(S(C)=O)nc21
Product: C[C@@H](CO)Nc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c(=O)n(C)c2n1
Yield: 45.4 %

Procedure:
Using the procedure in Example 57, 1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 43 (0.150 g, 0.311 mmol, 1.00 eq) and L-alaninol (48.4 μL, 0.622 mmol, 2.00 eq) were combined to afford (S)-1-(3-t-butylisoxazol-5-yl)-3-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (72 mg, 46% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d4): δ 10.34 (s, 1H), 8.73 (brs, 1H), 8.65 (brs, 1H), 8.39 (dd, J=2.4 and 8.0 Hz, 1H), 7.87 (s, 1H), 7.60-7.57 (m, 1H), 7.35-7.25 (m, 2H), 6.06 (s, 1H), 4.70 (t, J=6.0 Hz, 1H), 4.09 (brs, 1H), 3.58-3.49 (m, 4H), 3.35 (brs, 1H), 1.23 (s, 9H), 1.17-1.15 (m, 3H); MS (ESI) m/z: 510.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13](F)=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.[CH3:18][O:19][CH2:20][CH2:21][NH2:22].C(N(CC)CC)C>CCO.O>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][C:13]([NH:22][CH2:21][CH2:20][O:19][CH3:18])=[CH:14][CH:15]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: COCCN
Reactant: Nc1ncc(Br)cc1C(=O)c1ccc(F)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: COCCNc1ccc(C(=O)c2cc(Br)cnc2N)cn1
Reaction time: 0.25 h
Yield: 86 %

Procedure:
A solution of (2-amino-5-bromo-pyridin-3-yl)-(6-fluoro-pyridin-3-yl)-methanone, 2-methoxyethylamine (1 equiv.) and triethylamine (1.2 equiv.) in absolute EtOH (0.17 M) was sealed in a Smith process vial. The reaction was run in a Personal Chemistry® microwave reactor at 160° C. for 900 s. The mixture was diluted with water, and the resulting precipitate was filtered off, washed with water, and dried in vacuo to give (2-amino-5-bromo-pyridin-3-yl)-[6-(2-methoxy-ethylamino)-pyridin-3-yl]-methanone as a yellow solid (86% yield). 1H NMR (DMSO-d6): δ 8.28 (d, J=2.5 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.69 (dd, J=2.0, 9.0 Hz, 1H), 7.64 (broad s, 1H), 7.12 (broad s, 2H), 6.59 (d, J=9.5 Hz, 1H), 3.51 (t, J=4.5 Hz, 2H), 3.47 (t, J=4.5 Hz, 2H), 3.26 (s, 3H); HPLC/MS m/z: 351, 353 [MH]+.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:13][C@H:14]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:15][CH2:16][CH:17](C)C.Cl.[CH:32]1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][C@H:14]([C:20]([NH:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:21])[CH2:15][CH:16]([CH3:17])[CH3:32])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)CCC(C)C)C(N)=O
Agent: Cl
Agent: O=C1CCC(=O)N1O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C)C(N)=O
Yield: 51 %

Procedure:
Condensation of BocGlyOH (4.4 g.) and HLeu-MetNH2 hydrochloride salt (Example 1, 7.5 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocGly-Leu-MetNH2 in 51% yield. De-t-butoxycarbonylation of BocGly-Leu-MetNH2 using hydrogen chloride in acetic acid gave HGly-Leu-MetNH2 hydrochloride salt in 56% yield.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)(=[O:20])[CH3:19]>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([S:8]([NH:11][C:18](=[O:20])[CH3:19])(=[O:9])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1cccc(Br)n1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)NS(=O)(=O)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Bromopyridine-2-sulphonamide (0.5 g, 2.11 mmol, prepared by the methods described in WO2005/058299) and potassium carbonate (2.92 g, 21.1 mmol) were initially charged in acetonitrile (10 ml). While cooling with ice, acetyl chloride (1.16 g, 14.8 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, and the residue was taken up in water and acidified with dilute hydrochloric acid solution. It was extracted with ethyl acetate and the solvent was removed under reduced pressure. This gave 0.54 g (85% of theory) of N-[(6-bromopyridin-2-yl)sulphonyl]-acetamide.