Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]([N:19](C(OC(C)(C)C)=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[N:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:27].[ClH:35].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:19][C:9]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[NH:8])=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NC(=NCCCN1CCCC1)N(Cc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N=C(NCCCN1CCCC1)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of the product of step b (1.14 g, 2.00 mmol) in 1,4-dioxan (5 ml) was treated with hydrogen chloride in 1,4-dioxan (15 ml) and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated at reduced pressure. The residue was evaporated from DCM (30 ml) to give the title compound (700 mg, 95%). 1H NMR (DMSO-d6) 10.97 (1H, br s), 8.29 (1H, br s), 8.07 (1H, t, 6), 7.69 (2H, br s), 7.40 (2H, d, 8.4), 7.30 (2H, d, 8.4), 4.37 (2H, s), 3.48-3.45 (2H, m), 3.24-3.20 (2H, m), 3.08-3.03 (2H, m), 2.94-2.91 (2H, m), 2.00-1.84 (6H, m). Microanalysis found C 48.91 H 6.95 N 14.99. C15H25Cl3N4 requires C 48.99 H 6.85 N 15.24.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[O:10][CH3:11].ClC1C=CC(C)=C(OC)C=1.C1C(=O)[N:26](Br)[C:24](=O)C1>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:9][C:5]1[C:4]([O:10][CH3:11])=[C:3]([CH2:2][CH2:24][NH2:26])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1c(Cl)cccc1CBr
Reactant: O=C1CCC(=O)N1Br
Agent: COc1cc(Cl)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cccc1CCN
Temperature: 25 °C

Procedure:
1-(bromomethyl)-3-chloro-2-methoxybenzene. A mixture of 4-chloro-2-methoxy-1-methylbenzene (26.5 g, 169 mmol), NBS (33.1 g, 186 mmol) and benzoyl peroxide (200 mg, 0.826 mmol) in CHCl3 was heated to reflux for 24 h. The reaction was allowed to cool to RT and then concentrated in vacuo. The residue was stirred with petroleum ether and the resulting suspension was filtered off and the filtrate was concentrated in vacuo to give the title compound (30.9 g) as brown oil, which was used as it is in the next step. UPLC (2 min) rt 1.708 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.O1CCCC1.[CH3:14][NH2:15]>CO.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:15][CH3:14])[CH2:4][CH2:3]1
Reactant: CN
Reactant: CN1CCC(=O)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CCN(C)CC1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A mixture of 1-methyl-4-piperidone (20 g, 0.18 mol) in methanol:tetrahydrofuran (100 mL, 1:1) and methyl amine (2 M in tetrahydrofuran, 3 mole excess) was placed in a Parr shaker with 5% Pd/C and hydrogenated for two hours at 60 psi and 70° C. The catalyst was filtered and the filtrate concentrated on the rotary evaporator. The crude material was distilled at 44–45° C. at 0.3 mm Hg to give 20 g (87%) of 1-methyl-4-methylaminopiperidine. Anal. Calc'd for C7H16N2: C, 65.57; H, 12.58; N, 21.85. Found: C, 65.49; H, 12.44; N: 21,49.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[Br:17][C:18]1[N:26]2[C:21]([CH:22]=[N:23][C:24](S(C)=O)=[N:25]2)=[CH:20][CH:19]=1.CN1CCCC1=O>>[Br:17][C:18]1[N:26]2[C:21]([CH:22]=[N:23][C:24]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CS(=O)c1ncc2ccc(Br)n2n1
Solvent: CN1CCCC1=O
Product: COCCN1CCc2ccc(Nc3ncc4ccc(Br)n4n3)cc2CC1
Temperature: 135 °C
Yield: 62.5 %

Procedure:
Into a 30 ml, vial, [A] 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (0.242 g, 0.00110 mol), [B] 7-Bromo-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.130 g, 0.000500 mol), and N-Methylpyrrolidinone (0.39 mL, 0.0041 mol) were added. The reaction mixture was heated at 135° C. for 7 hours. The reaction mixture was purified via ISCO column chromatography with EtOAc and methanol as eluant (5 to 20% methanol). The collected fractions afforded (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-amine as a yellow solid (130 mg, 65%). NMR 1H (CDCl3-d)-8.57 (s, 1H), 7.54 (s, 1H), 7.48 (dd, 1H, JJ=1.96, 6.04 Hz), 7.69 (s, 1H), 7.09 (d, 1H, J=8.04 Hz), 6.93 (s, 1H), 6.78 (d, 1H, J=4.72 Hz), 6.73 (d, 1H, J=4.72 Hz), 3.54 (t, 2H, J=5.68 Hz), 3.36 (s, 3H), 2.65-3.00 (m, 10H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[CH:18]([N-]C(C)C)(C)C.[Li+].IC.O>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10]([CH3:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1
Reactant: CCOC(=O)C1CCN(c2ccncn2)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN(c2ccncn2)CC1
Reaction time: 8 h

Procedure:
1-(4-pyrimidinyl)-4-(ethoxycarbonyl)piperidine (400 mg) in 4 ml tetrahydrofuran was cooled to -70° C and treated with a solution of lithium diisopropylamide (1.0 ml in THF), under an argon atmosphere. After stirring 1.5 hours 1.2 ml of a solution of 1 ml iodomethane in 10 ml THF was added and reaction mixture left to reach room temperature overnight. Water added and extracted twice with ethyl acetate. Organic extract washed with brine and dried over magnesium sulphate, filtered and evaporated to give 1-(4-pyrimidinyl)-4-methyl-4-(ethoxycarbonyl)piperidine (370 mg) as an oil; NMR (CDCl3): 1.24 (s, 3H), 1.28 (t, 3H), 1.38-1.51 (m,2H), 2.14-2.26 (m, 2H), 3.12-3.26 (m, 2H), 4.03-4.14 (m, 2H), 4.2(q,2H), 6.5 (dd, 1H), 8.17 (d. 1H), 8.57 (s, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:15][CH:12]1[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cncc(Br)c1Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cncc(Br)c1NC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step 2 (8.01 g, ca. 30 mmol) in dichloromethane (100 ml) at 0° C. was added cyclopropylamine (4.16 ml, 60 mmol) drop-wise. The resulting mixture was stirred overnight at room temperature, then concentrated under vacuum to a residue and re-dissolved in ethyl acetate, basifying with sodium bicarbonate. The organic phase was washed with water three times, followed by twice with brine before concentrating under vacuum to a crude solid. This oil was purified by column chromatography eluting with a gradient of 50% DCM/hexane to DCM affording product as a yellow solid, 6.22 g (80%); MS (ES+) m/e 258/260 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1)=[O:5].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(C)(C)CC(=O)c1ccc(CBr)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)CC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
Add 4-(3,3-dimethyl-butyryl)-benzyl bromide (1 g, 3.731 mmol) to a stirred suspension of potassium phthalimide (0.705 g, 3.805 mmol) in anhydrous DMF (20 mL). Stir the mixture overnight at room temperature. Dilute with EtOAc and wash twice with ice-cold water. Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane and hexane/EtOAc (19:1, 4:1) to provide the desired intermediate as oil (1.24 g, 100%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Na].[CH3:23][OH:24]>O>[CH3:23][O:24][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)nn2)CC1
Reactant: CO
Agent: [Na]
Solvent: O
Product: COc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nn1
Temperature: 120 °C
Yield: 75 %

Procedure:
tert-Butyl [1-(6-chloropyridazin-3-yl)piperidin-4-yl]carbamate (0.50 g, 1.60 mmol) was dissolved in dry MeOH (15 ml) and sodium metal (0.073 g, 3.20 mmol) dissolved in MeOH (5 ml) was added. The reaction mixture was heated at in a microwave reactor at 120° C. for 4 h. The mixture was diluted with water (500 ml) and extracted with EtOAc (200 ml). The organic phase was dried (Na2SO4), filtered and evaporated to yield the title compound (0.37 g, 75%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH3:25])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH3:25])[CH:17]=1
Reactant: COc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: COc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-methoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.89 (3H, s), 5.22 (2H, s), 5.78 (1H, d, J=2.0 Hz), 6.92 (1H, d, J=2.0 Hz), 6.95-6.98 (1H, m), 7.33-7.35 (1H, m), 7.39 (1H, dd, J=1.2, 5.2 Hz), 7.57-7.58 (1H, m), 8.06 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C17H13ClN4O2, 341; Found, 341.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: C1CCCNCC1
Product: Cc1nc2ccc(N3CCCCCC3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 32 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and azepane according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 32%; MS: m/z=431 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](I)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:22](B(O)O)=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.O.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.CO>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc([N+](=O)[O-])cc21
Reactant: OB(O)C=Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc([N+](=O)[O-])cc21
Temperature: 90 °C
Yield: 74.1 %

Procedure:
To 6-nitro-3-iodo-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (11.0 g, 26.1 mmol), styryl boronic acid (4.64, 31.4 mmol), and Pd(PPh3)4 (1.25 g, 1.08 mmol) under an atmosphere of argon was added toluene (192 mL), MeOH (4 mL) and 2N NaOH (aq) (32.6 mL, 65.3 mmol). The resulting heterogeneous mixture was heated to 90° C. After 8 h the reaction was diluted with EtOAc (150 mL) and water (50 mL), the phases were separated and the organic was extracted 2×50 mL EtOAc. The pooled organic phase was washed with brine (50 mL), then dried with Na2SO4, filtered and concentrated under reduced pressure. The crude reaction was purified by silica gel chromatography (1:9 EtOAc:hexane) to give 6-nitro-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a yellow solid (7.65 g, 74%): 13C NMR (75 MHz, CDCl3) δ 148.3, 145.0, 141.3, 138.1, 134.2, 130.5, 129.9, 129.8, 129.5, 128.1, 127.4, 123.2, 119.8, 117.8, 108.2, 79.7, 68.5, 19.2, 0.0; MS (FAB) [M+Na]/z Calc'd 418. found 418. Anal. Calc'd: C, 63.77; H, 6.37; N, 10.62. Found: C, 64.04; H, 6.29; N, 10.56.
Reaction SMILES: B.[NH2:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[C:5]#[N:6].C(O)C.[ClH:17]>C1COCC1>[ClH:17].[NH2:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH2:5][NH2:6]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Borane in THF (400 ml, 0.40 mol) is added dropwise to 2-amino-5-nitrobenzonitrile (60 g, 0.35 mol) in THF (600 ml) at 0° C. The mixture is allowed to warm to room temperature and is stirred for 16 hours. The resulting mixture is cooled to 0° C. and 200 ml of absolute ethanol/HCl are added. The THF is removed and the product is filtered off and recrystallized from isopropyl ether. Yield: 68.8 g (96%); Rf (1:1 methanol/chloroform): 0.15; IR (KBr): 3416, 2980, 1669, 1601, 1474, 1285 cm−1.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]([C:14]2[N:18]([CH3:19])[N:17]=[CH:16][C:15]=2[Cl:20])[N:4]=1.C(OC(=O)[NH:27][CH2:28][C@@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl>C(O)CCC.C1COCC1>[NH2:27][CH2:28][C@@H:29]([N:37]1[C:9](=[O:11])[C:8]2[CH:7]=[N:6][C:5]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[Cl:20])=[N:4][C:3]=2[CH2:2]1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cnc(-c2c(Cl)cnn2C)nc1CBr
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCCCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1ncc2c(n1)CN([C@H](CN)Cc1ccccc1)C2=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A mixture of ethyl 4-(bromomethyl)-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)pyrimidine-5-carboxylate (284.0 mg, 0.7898 mmol), tert-butyl[(2S)-2-amino-3-phenylpropyl]carbamate (198 mg, 0.791 mmol), and N,N-diisopropylethylamine (0.275 mL, 1.58 mmol) in 1-butanol (5.0 mL) was stirred at 140° C. for 2 h. The reaction mixture was evaporated under reduced pressure to give an oil residue, which was dissolved in 4 M HCl aqueous solution (2 mL, 8 mmol) and THF (2 mL). The resulting solution was stirred at room temperature for 1 hour. Direct purification on prep.HPLC afforded 81 mg (25.6% yield) of the desired product. LC-MS found: 383.1 (M+H)+.
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N:9]3[C:13]4[CH:22]=[CH:21][C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=5[N+:14]=4[CH:23]=[C:8]3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CO>[I-:1].[N:24]1([C:3]2[CH:12]=[CH:11][C:10]3[N:9]4[C:13]5[CH:22]=[CH:21][C:20]6[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=6[N+:14]=5[CH:23]=[C:8]4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNC1
Reactant: Fc1ccc2c(ccc3c[n+]4c5ccccc5ccc4n32)c1
Agent: [I-]
Solvent: CO
Product: c1ccc2c(c1)ccc1n3c(ccc4cc(N5CCCC5)ccc43)c[n+]21
Temperature: 190 °C

Procedure:
A mixture of 4.14 g. of 10-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 3.6 g. of pyrrolidine and 100 ml. of methanol is stirred and heated in a pressure vessel at 190° C. for 24 hours, then cooled and evaporated at reduced pressure. The resulting precipitate of 10-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected and washed with cold methanol; m.p. 350°-355° C., after crystallization from dimethylformamide.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH2:13][C:14]([O:16]C)=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].Cl>CO>[Cl:3][C:4]1[CH:9]=[C:8]([S:10]([CH2:13][C:14]([OH:16])=[O:15])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: COC(=O)CS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)CC(=O)O)cc1Cl)C(F)(F)F
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Sodium hydroxide (2.5 ml of a 2M aqueous solution) was added to a stirred solution of (R)-N-[2-chloro-4-(methoxycarbonylmethylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 142) (0.36 g) in methanol (6 ml) and the mixture was stirred for 1 hour. Hydrochloric acid (3 ml of a 2M aqueous solution) was added and volatile material was removed by evaporation. Ethyl acetate (80 ml) was added and the mixture washed with brine (50 ml), dried and volatile material removed by evaporation. The residue was dissolved in DCM (50 ml), washed with saturated sodium hydrogen, carbonate solution (100 ml). The aqueous layer was treated with hydrochloric acid (25 ml, 10% v/v) and extracted into ethyl acetate (2×100 ml) and dried. Volatile material was removed by evaporation to give the title compound (0.28 g) as a foam. NMR: 1.62 (s, 3H), 4.57 (s, 2H), 7.9 (d, 2H), 8.02 (s, 1H), 8.06 (s, 1H), 8.32 (d, 1H). 9.92 (s, 1H); MS (ESP−): 388.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(Cl)([Cl:24])=O>C1C=CC=CC=1>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:24])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-dodecyloxybenzyl alcohol (Preparation 1, 2.92 g, 0.0010 M) in benzene (40 mL) is added dropwise to a stirred solution of thionyl chloride (3.0 mL, 4.97 g, 0.04 M) over a period of 20 minutes. The solution is stirred at room temperature for 0.5 hr and then is heated at reflux temperature for 3 hours (monitoring of the reaction by TLC may be deceptive since the product is hydrolyzed to starting alcohol when placed on a silica gel plate; the plate must be developed immediately after the sample is applied). Benzene and excess thionyl chloride are removed under reduced pressure. The crude product is used in Example 1 without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:16][C:17]1[CH:22]=[CH:21]C(C2C=CC(C(O)=O)=CC=2)=[CH:19][CH:18]=1.S(Cl)(Cl)=O.CC(C)([O-])C.[Li+]>>[Br:16][C:17]1[CH:22]=[CH:21][C:15]([C:14]2[CH:13]=[CH:12][C:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1Br
Reactant: O=C(O)c1ccc(-c2ccc(Br)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(Br)cc2)cc1

Procedure:
Compound 210.1 was prepared as described for the preparation of 183.1 from 4′-bromobiphenyl-4-carboxylic acid, thionyl chloride and lithium tert-butoxide.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[S:11][C:12]3[CH2:19][CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:15]=4[C:13]=3[N:14]=2)[CH2:5][CH2:4]1.[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29].O>N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[F:24][C:22]1[CH:21]=[CH:20][C:16]2[CH2:17][CH2:18][CH2:19][C:12]3[S:11][C:10]([NH:9][CH:6]4[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:4][CH2:5]4)=[N:14][C:13]=3[C:15]=2[CH:23]=1
Reactant: NC[C@H]1CC[C@H](Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)NCC1CCC(Nc2nc3c(s2)CCCc2ccc(F)cc2-3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a stirred, septum capped solution of trans-N2-[4-(aminomethyl)-cyclohexyl]-9-fluoro-5,6-dihydro-4H-benzo[6,7]-cyclohepta[d][1,3]thiazol-2-amine (5.00 g, 11.95 mmol) in anhydrous pyridine (20 ml) and diisopropylethylamine (10 ml) was added methoxyacetyl chloride (1.20 ml, 13.1 mmol) dropwise. The solution was stirred at room temperature for 2 hours and was then poured into 250 ml water and extracted with 250 ml EtOAc. The extract was evaporated to yield a golden viscous oil which was chromatographed on silica-gel eluting with EtOAc to yield 88% (4.40 g) of the desired product as a slightly yellow solid. A small portion of the product was recrystallized from EtOAc (m.p. 95-97° C.). The free-base was dissolved in 60 ml CHCl3 and converted to its HCl salt by adding 14.0 ml 1.0 N HCl in ether followed by evaporation of the solvent. The resulting foam was stirred with ether (75 ml), filtered and washed with ether to yield the HCl salt as a solid: 1H-NMR (Free-base) (CDCl3) δ 1.12 (4H, m), 1.45 (1H, m), 1.81 (2H, m), 2.05 (2H, m), 2.21 (2H, m), 2.80 (4H, m), 3.16 (2H, t, J=6.5 Hz), 3.25 (1H, m), 3.41 (3H, s), 3.89 (2H, s), 5.03 (1H, d, J=8.0 Hz), 6.62 (1H, broad t), 6.81 (1H, dt, J=2.9, 8.3 Hz), 7.03 (1H, m), 7.69 (1H, dd, J=2.8, 10.8 Hz) m.p. 63-65° C. Anal. Calcd. For C22H29N3O2SFCl+0.5CHCl3: C, 52.61; H, 5.79; N, 8.18. Found: C, 52.61; H, 5.92; N, 8.08; 418 (ESMS, MH+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH2:62][C@H:61]([NH2:65])[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][C@H:61]5[CH2:62][CH2:63][CH2:64][N:59]([CH3:58])[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC[C@H](N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CCCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-methylpiperidin-3-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.26 (m, 2 H) 1.29-1.46 (m, 3 H) 1.55-1.73 (m, 5 H) 1.75-1.90 (m, 6 H) 2.23 (br s, 3 H) 2.64-2.78 (m, 1 H) 2.79-2.95 (m, 1 H) 3.31 (s, 3 H) 3.90-4.01 (m, 1 H) 3.94 (s, 3 H) 4.07 (t, J=12.63 Hz, 2 H) 4.37-4.53 (m, 1 H) 7.47 (dd, J=8.46, 1.64 Hz, 1 H) 7.51 (d, J=1.77 Hz, 1 H) 7.91 (s, 1 H) 8.10 (d, J=7.33 Hz, 1 H) 8.21 (s, 1 H) 8.27 (d, J=8.34 Hz, 1 H). [M+H] calc'd for C28H37F2N7O3 558; found 558.