Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)(=[O:3])[CH3:2].[BrH:13].C(O)(=O)C.BrBr>C(O)(=O)C>[Br:13][CH2:2][C:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)=[O:3]
Reactant: Br
Reactant: CC(=O)c1cnc2ccccn12
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cnc2ccccn12
Temperature: 40 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
22.1 g of 3-acetylimidazo[1,2-a]pyridine was dissolved in 220 ml of acetic acid. 35.1 ml of a 30% hydrogen bromide/acetic acid solution was added dropwise to the solution at 0° C. Then 28.6 g of bromine was added dropwise thereto at 40° C. The mixture was stirred at 40° C. for 2 h and crystals thus formed were filtered. The crystals were dissolved in 100 ml of water. The solution was made alkaline with an excess of an aqueous sodium hydrogencarbonate solution and then extracted with ethyl acetate. The organic layer was concentrated and the obtained brown solid was purified according to silica gel column chromatography (eluted with ethyl acetate) to obtain 13.5 g (yield: 40%) of 3-bromoacetylimidazo[1,2-a]pyridine (yield: 40%) in the form of yellow crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[N:2]1.[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([NH2:32])=[CH:31][C:25]=2[N:24]=1)([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[NH:24][C:25]2[CH:31]=[C:30]([NH:32][C:10]([C:7]3[CH:8]=[C:9]4[C:4]([CH:3]=[N:2][NH:1]4)=[CH:5][CH:6]=3)=[O:12])[CH:29]=[CH:28][C:26]=2[N:27]=1)([CH3:15])[CH3:14]
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: CC(C)c1ccccc1Nc1nc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(NC(=O)c3ccc4cn[nH]c4c3)cc2[nH]1

Procedure:
Methyl Indazole-6-carboxylate (4 mmol; Batt et al, J. Med. Chem. 2000, 43, 41-58) was hydrolyzed as in general procedure C to obtain 1H-Indazole-6-carboxylic acid. The carboxylic acid (0.5 mmol) was coupled with aforementioned N2-(2-isopropylphenyl)-1H-benzimidazole-2,5-diamine (0.5 mmol) using HBTU as described in general procedure D to yield 1H-indazole-6-carboxylic acid [2-(2-isopropylphenylamino)-3H-benzimidazol-5-yl]-amide as an off-white solid. MS: m/z 411 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)[CH2:3][CH:4]=O.[CH:30]([NH2:33])([CH3:32])[CH3:31].C([BH3-])#N.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClC(Cl)C.C(Cl)Cl.C(O)(=O)C>[CH:30]([NH:33][CH2:4][CH2:3][CH:2]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:29])[CH:13]([NH:17][C:18](=[O:28])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH2:14][CH2:15][CH3:16])=[N:8][N:7]=1)[CH3:1])([CH3:32])[CH3:31]
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)CC=O)s1
Reactant: CC(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)CCNC(C)C)s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-methyl-3-oxo-propyl)-[1,3,4]thiadiazol-2-yl]-amide (63 mg, 0.148 mmol), isopropylamine (0.2 ml) in dichloroethane (1 ml) and methylene chloride (1 ml) was stirred at r.t. for 10 min. Sodium cyanoborohydride (70 mg), acetic acid (0.1 ml), and sodium sulphate were added and the resulting mixture was stirred at 45-50° C. overnight. The mixture was quenched with water, basified with saturated sodium carbonate, extracted with methylene chloride. The organic layer was separated, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by Shimadzu HPLC to give the title compound LC-MS RT=1.7 min, M+1=467.9.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([NH:14][C:15]([O:17]C(C1CO1)=O)=O)[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:23].[K+].[CH2:25]([OH:27])[CH3:26].O.Cl.[CH2:30]([OH:32])C>>[OH:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:26]1[O:27][C@@H:25]1[C:30]([OH:32])=[O:23])=[O:17])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)C[C@H](NC(=O)OC(=O)C1CO1)[C@H](O)c1ccccc1
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H]1O[C@@H]1C(=O)O)[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl (2S,3S)-3-[[1-(S)-[α-(R)-hydroxybenzyl]-3-methylbutyl carbamoyl]oxirane-2-carboxylate (558 mg, 1.66 mmol.) in ethanol (4 mL) was dropwise added 0.5N potassium hydroxide/ethanol solution (4.0 mL, 2.0 mmol.) under chilling with ice The mixture was stirred for 4 hours at room temperature, and made acidic to reach pH 1-2 by addition of water (40 m) and 2N hydrochloric acid (approx. 2 mL). The acidic mixture was extracted with three portions of ethyl acetate. The three extracts were combined and washed successively with water and an aqueous saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the titled compound as a white amorphous product (490 mg, yield 96%).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:23][C@H:24]([NH2:27])[CH2:25][CH3:26]>CS(C)=O.O>[C@@H:24]([NH:27][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:25][CH3:26])[CH3:23]
Reactant: CC[C@H](C)N
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: O
Solvent: CS(C)=O
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (400.0 mg, 1.26 mmol) in DMSO (3 mL) was added (S)-butan-2-amine (200 mg, 2.74 mmol). The resulting solution was stirred overnight at 90° C. and then diluted with water (50 mL), extracted with dichloromethane (5×20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 2% ethyl acetate in petroleum ether to afford (S)-methyl 3-(sec-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (280.0 mg, 63%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][C:17]([OH:19])=O)([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:23])=O>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][C:17]([Cl:23])=[O:19])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)O)c(C(C)C)c1
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(C)C)c(CC(=O)Cl)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 2,4,6-triisopropylphenylacetic acid (6.03 g, 0.023 mol), oxalyl chloride (20 mL), and dimethylformamide (3 drops) was stirred vigorously at room temperature and then allowed to stand overnight at room temperature. The reaction mixture was then concentrated to give the product as an off-white solid 6.5 g, 100%. This was used directly in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[C:22]([CH3:29])[CH:21]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[C:22]([CH3:29])[CH:21]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(N)ccc1CC#N
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: Cc1cc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)ccc1CC#N
Yield: 46.5 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with 2-(4-amino-2-methylphenyl)acetonitrile (0.073 g, 0.50 mmol), followed by the formation of the hydrochloride salt to afford the title compound (0.063 g, 63%) as a white solid. MW=410.34. 1H NMR (DMSO-d6, 500 MHz) δ 13.96 (s, 1H), 9.71 (s, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.78-7.69 (m, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 4.03 (s, 2H), 3.14 (t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.34 (s, 3H), 2.28-2.19 (m, 2H); APCI MS m/z 374 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].Cl.Cl.[N:31]1([CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32]1>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:20]([N:39]2[CH2:40][CH2:41][CH:36]([CH2:35][N:31]3[CH2:34][CH2:33][CH2:32]3)[CH2:37][CH2:38]2)=[O:21])[CH:6]=1
Reactant: C1CN(CC2CCNCC2)C1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(CN2CCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (200 mg) was dissolved in tetrahydrofuran (8 ml) under a nitrogen atmosphere, and then triethylamine (0.335 ml) and phenyl chloroformate (0.300 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 30 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added N,N-dimethylformamide (3 ml). 4-(Azetidin-1-ylmethyl)piperidine dihydrochloride (600 mg) and triethylamine (0.781 ml) were added thereto, followed by stirring for 7 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:8, then ethyl acetate). Fractions containing the target compound were concentrated to provide a crude product of the titled compound (340 mg) as a pale yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.OS(O)(=O)=O.[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[CH:28]4)=[CH:22][C:17]=2[O:16][CH2:15]1>C1COCC1.CCOC(C)=O>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[C:24]4[CH2:38][O:37][C:36](=[O:39])[C:25]=4[CH:26]=[C:27]4[C:35]=3[C:31]3[O:32][CH2:33][O:34][C:30]=3[CH:29]=[C:28]4[Br:1])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1OCc2c1cc1c(Br)cc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.8 %

Procedure:
N-bromosuccinimide (10.7 mg, 0.06 mmol) and concentrated H2SO4 (5 μL) were added to a solution of 2 (15.4 mg, 0.044 mmol) in THF (1 mL). The solution was stirred at room temperature for 20 h, and then diluted with EtOAc (30 μL). The same workup and purification procedure as described for the isolation of 37 gave 38 (12 mg, 64%) as a pale yellow powder. mp 256° C. (decomp.); 1H NMR (CDCl3) δ 8.89 (s, 1H, H4), 7.65 (s, 1H, H6), 6.76-6.91 (m, 3H, H2′+H5′+H6′), 6.08 (AB, 2H, 3′,4′-OCH2O—, Δδ=8.7 Hz, J=1.5 Hz), 5.97 (AB, 2H, 7,8-OCH2O—, Δδ=7.8 Hz, J=1.5 Hz), 5.22 (q, 2H, lactone-CH2—, J=8.4 Hz); MS (EI) m/z 428 [M+2]+, 426 [M]+.
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:3][N:4]=[C:5]1NC2C=CC=CC=2O[CH:6]1[CH3:15].[BH4-].[Na+].[OH2:23].[C:24]([O:27][CH2:28][CH3:29])(=O)[CH3:25]>CO>[CH3:25][C@@H:24]1[C:5](=[O:23])[NH:4][C:3]2[CH:2]=[C:6]([CH2:5][NH:4][CH2:3][C:2]([F:1])([F:20])[C:16]([F:17])([F:18])[F:19])[CH:15]=[CH:29][C:28]=2[O:27]1
Reactant: CCOC(C)=O
Reactant: CC1Oc2ccccc2NC1=NCC(F)(F)C(F)(F)F
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1Oc2ccc(CNCC(F)(F)C(F)(F)F)cc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
712 mg (2.21 mmol) of (2R)-methyl-3-oxo-6-(2,2,3,3,3,-pentafluoropropylimino-methyl-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 30 ml of methanol and mixed with 83.6 mg (2.21 mmol) of sodium borohydride. After stirring overnight at room temperature, the batch is added to water and shaken three times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried and spun in. After chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 396.7 mg (55%) of the desired compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH3:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH3:26])[C:3]=1[O:27][C@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: Cc1cc(-c2c3ccccc3c(C)c3sc4ccccc4c23)cc(C)c1O
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: Cc1cc(-c2c3ccccc3c(C)c3sc4ccccc4c23)cc(C)c1O[C@H](Cc1ccccc1)C(=O)O

Procedure:
Prepared from of 2,6-dimethyl-4-(6-methyl-benzo[b]naphtho [2,3-d]thiophen-11-yl)-phenol (Example 25) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: NMR (DMSO-d6); δ13.0 (broad band, 1 H), 8.18 (d, J=8 Hz, 1 H), 7.91(d, J=8 Hz, 1 H), 7.61 - 7.53 (m, 2 H), 7.43 (ddd, J=8, 7, 1 Hz, 1 H), 7.45 - 7.28(m, 5 H), 7.25 - 7.21 m, 1 H), 7.01 (ddd, J=8, 7, 1 Hz, 1 H), 6.95 (d, J=5 Hz, 2 H), 6.53 (d, J=8Hz, 1 H), 4.75 (t, J=7 Hz, 1 H), 3.32 - 3.24 (m, 2 H), 2.87 (s, 3 H), 2.56 (s, 3 H), 2.18 (s, 3 H): MS(EI): [M+] 516; Anal. Calc. for C34H28O3S: C, 79.04, H, 5.46, N, 0.00. Found: C, 79.13, H, 5.41, N, 0.11.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]=1)=[O:7].[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>O1CCOCC1>[ClH:3].[Cl:3][C:4]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH:10]=1)=[O:7]
Reactant: CN1CCC(Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCC(N(C(=O)C2CC2)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 106 °C
Yield: 172.8 %

Procedure:
Combine 2-chloro-4-fluoro-N-(3-(1-methylpiperidin-4-ylamino)phenyl)benzamide dihydrochloride (Example 1, 48 mg, 0.134 mmol), dioxane (1 mL) and cyclopropylcarbonyl chloride (0.013 mL, 0.148 mmol). Shake and heat (106° C.) in a J-Kem® Reaction Block for 2 hr. Load onto a SCX column (Varian) and elute with 2 M ammonia methanol to give the free base of the title compound (54 mg, 93%). Following a salt formation method similar to that described in Example 1 gives the title compound as a white solid (47 mg): mp 133-6° C.; mass spectrum (freebase, ion spray): m/z=430.1 (M+1), 1H NMR (freebase, CDCl3): 8.31 (bs, N—H), 7.76 (dd, J=6.0 Hz, 8.6 Hz, 1H), 7.61-7.56 (m, 2H), 7.38 (t, J=8.0 Hz, 1H), 7.19 (dd, J=2.4 Hz, 8.3 Hz, 1H), 7.09 (td, J=2.4 Hz, 8.2 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H), 4.62-4.53 (m, 1H), 2.80 (bd, J=11.5 Hz, 2H), 2.20 (s, 3H), 2.05 (td, J=2.2 Hz, 12.1 Hz, 2H), 1.83-1.69 (bm, 2H), 1.59-1.37 (bm, 2H), 1.21-1.13 (m, 1H), 0.99-0.89 (bm, 2H), 0.56 (bd, J=7.4 Hz, 2H). Analysis calc'd for C23H26Cl2FN3O2.0.8H2O: C, 57.46; H, 5.79; N, 8.74. Found: C, 57.16; H, 5.73; N, 8.70.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12](O)[CH3:13]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: CCO
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(C)nc(Cl)c1
Yield: 86 %

Procedure:
A solution of 2-chloro-6-methyl-4-pyridinecarboxylic acid (2 g, 12 mmol) in ethanol (100 ml) and concentrated sulphuric acid (10 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was dissolved in methylene chloride. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1/9) to give ethyl 2-chloro-6-methyl-4-pyridinecarboxylate (2 g, 86%). 1H NMR Spectrum: (CDCl3) 1.41(t, 3H); 2.6(s, 3H); 4.40(q, 2H); 7.63(s, 1H); 7.69(s, 1H) MS-ESI: 200 [MH]+
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH2:28][NH:27][CH2:26][CH2:25]5)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH2:28][N:27]([CH3:34])[CH2:26][CH2:25]5)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3ccc4c(c3)CCNC4)cc3nccn23)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCc2cc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-6-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 52; 10 mg, 0.024 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (49 mg, 0.49 mmol) and sodium triacetoxyborohydride (16 mg, 0.073 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=424.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[N:33]=[C:34]=[O:35]>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[NH:33][C:34]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:20][CH3:21])=[O:35]
Reactant: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1N
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: CSc1cc(Oc2ccnc3ncc(=O)[nH]c23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 73 %

Procedure:
Using Method F2 with 8-(4-amino-3-(methylthio)phenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound (37 mg, 73%) was obtained as a powder.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[F:11][C:12]1[CH:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2)=[N:16][CH:17]=1.[F:32][C:33]1[C:42]2[C:37](=CC=CC=2)[C:36]([C:43](Cl)=[O:44])=[CH:35][CH:34]=1.Cl>C1COCC1.C(Cl)Cl>[F:32][C:33]1[CH:42]=[CH:37][C:36]([C:43]([CH:26]([CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][N:18]([C:15]3[N:16]=[CH:17][C:12]([F:11])=[CH:13][N:14]=3)[CH2:23][CH2:22]2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:44])=[CH:35][CH:34]=1
Reactant: CCOC(=O)CCCN1CCN(c2ncc(F)cn2)CC1
Reactant: O=C(Cl)c1ccc(F)c2ccccc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(CCN1CCN(c2ncc(F)cn2)CC1)C(=O)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a cold (-78° C.) solution of lithium 1,1,1,3,3,3-hexamethyl disilazane in tetrahydrofuran (27.4 mL, 1N, 27.4 mmol) kept under Ar atm was added dropwise (10 min) a solution of ethyl 4-(4-(5-fluoro-2-pyrimidinyl)piperazin-1-yl)butanoate (3.7 g, 12.5 mmol) in dry THF (12 mL). The reaction mixture was stirred 0.25 h at -78° C. and then treated dropwise (10 min) with a solution of 4-fluoro-1-naphthoyl chloride (2.6 g, 12.5 mmol) in dry THF (10 mL). The reaction was stirred -78° C. for 0.5 h then the cooling bath was removed. When the temperature of reaction mixture reached 0° C., HCl solution (40 mL, 0.3N) was added slowly followed by CH2Cl2 (350 mL); the organic phase was separated and aqueous phase was extracted with CH2Cl2 (120 mL). The organic extracts were combined, washed with water (2×45 mL) and brine, dried (MgSO4) and concentrated under reduced pressure to a crude mixture which was purified on a silica gel pad (8.7×2.5 cm). Evaporation of appropriate fractions gave 2.8 g (48%) of the desired product compound which was recrystallized from EtOH to give an analytical sample; mp 95°-6° C.; 1H NMR (CDCl3, 200 MHz) δ: 1.08 (t, J=7.1 Hz, CH3, 3H), 2.1-2.7 (m, 8H), 3.5-3.8 (m, 4H), 3.9-4.3 (m, 2H), 4.5-4.7 (m, 1H), 7.1-7.25 (m, 1H), 7.5-7.8 (m, 2H), 8.17 (s), 8.0-8.02 (s and m, 4H), 8.6-8.7 (m, 1H); IR (KBr) ν: 1740 (C=O, 1682, 1630, 1611, 1600, 1578, 1554, 1510 cm-1 ; UV (CH3CN) λ: 224 (ε 43570), 242 (ε 37740), 304 (ε 9084);
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][CH:14]1[CH2:17][CH2:16][CH2:15]1.CN([CH:21]=[O:22])C.O>C1COCC1>[CH:14]1([S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:21]=[O:22])[CH2:17][CH2:16][CH2:15]1
Reactant: Brc1ccccc1SC1CCC1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccccc1SC1CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of n-butyllithium (7.35 mL of a 1.6 M solution in hexanes, 11.7 mmol) in dry THF (15 mL) at −78° C. was added dropwise over 10 minutes a solution of (2-bromophenyl)(cyclobutyl)sulfane (1.19 g, 4.89 mmol) in dry THF (15 mL) and the resulting solution stirred at −78° C. for 30 minutes. Anhydrous DMF (1.14 mL, 14.7 mmol) was then added, and the solution stirred at −78° C. for 5 minutes, before allowing to warm to room temperature and stirring for a further 1 hour. Water was then added, and the volatiles removed in vacuo, before extracting the mixture with ethyl acetate (×3). The combined organics were washed with brine, then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified using flash column chromatography on silica gel (eluting with a gradient of 0 to 5% ethyl acetate) to afford 2-(cyclobutylthio)benzaldehyde (450 mg, 2.34 mmol, 48%).