Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][Br:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(CBr)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
Into a reaction flask equipped with a mechanical stirrer, thermometer and reflux apparatus was charged 75 grams (0.5 moles) of p-methylphenyl acetate prepared in Part A, 88 grams (0.5 moles) of N-bromosuccinimide, 300 milliliters of carbon tetrachloride and 1.0 gram of benzoyl peroxide. The resulting reaction mixture was carefully heated to 80° C. with a mantle, at which temperature, slight reflux ensued along with an exothermic reaction. Reflux was carefully maintained for 40 minutes and then 200 milliliters of carbon tetrachloride was gradually added to the reaction flask and the reaction mixture was then cooled to 25° C. (total time from onset of reflux was 50 minutes). The reaction mixture was filtered on a Buchner funnel and after the collected solid (succinimide) was washed four times with 100 milliliters of carbon tetrachloride, the total carbon tetrachloride solution (filtrate and washes) was stripped on a rotary evaporator. The resulting residue was distilled at reduced pressure (0.4 torr) to give a total of 92.8 grams of the desired product, whose nuclear magnetic resonance (NMR) spectrum was consistent with bromination of the aromatic methyl group: 2.13δ, singlet, CH3O; 4.28, singlet, BrCH2 --; and 6.97, quartet, aromatic protons.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:9].CC1(C)C(C)(C)OB([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)O1>>[Cl:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Reactant: Fc1cccc(Cl)c1Br
Product: Fc1cccc(Cl)c1-c1ccc2[nH]ccc2c1
Yield: 62.7 %

Procedure:
This title compound was prepared analogously to compound 25b using 2-bromo-1-chloro-3-fluorobenzene (39.5 g, 0.19 mol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (37.0 g, 0.15 mol). The title compound (23.1 g, 62%) was obtained. MS (ESI, m/z): 246.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[N:5]=1)([CH3:3])=[CH2:2].[Cl:12]N1C(=O)CCC1=O.C(OO)(C)(C)C>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[N:5]=1)=[CH2:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=C(C)c1cccc(OC)n1
Agent: CC(C)(C)OO
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(CCl)c1cccc(OC)n1
Temperature: 140 °C
Reaction time: 5 h

Procedure:
A mixture of 13.6 g of 2-isopropenyl-6-methoxypyridine, 16.3 g of N-chlorosuccinimide, 0.2 g of t-butylhydroperoxide and 30 ml of carbon tetrachloride was stirred at 140° C. for 5 hours while being irradiated with light. After the reaction mixture was cooled to room temperature, the insoluble matter was filtered out. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (eluted with ethyl acetate-n-hexane 1:25) to obtain the following three fractions: 4.75 g of a first fraction (objective product/byproduct=0.2), 5.99 g of a second fraction (objective product/byproduct=0.714) and 0.41 g of a third fraction (objective product=1.0).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:21]3[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Yield: 94.7 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), then ethyl isonipecotate (0.12 ml, 0.78 mmol) and diisopropylethylamine (0.15 ml, 0.88 mmol) were added, followed by heating under reflux for 3 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1) to obtain a yellow oil (0.27 g, 94%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:29])[C:9](=[O:28])[NH:10][C:11]1[N:12]=[C:13]([C:21]#[C:22][C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:29])[C:9]([NH:10][C:11]1[N:12]=[C:13]([C:21]#[C:22][C:23]2[N:24]=[CH:25][S:26][CH:27]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:28]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#Cc2cscn2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)Nc1cc2ccccc2c(C#Cc2cscn2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl-N-[1-oxo-1-[[1-[2-(1,3-thiazol-4-yl)ethynyl]isoquinolin-3-yl]-amino]propan-2-yl]carbamate E4b (12 mg, 0.03 mmol) and DCM:TFA (9:1, 3 ml) is stirred at RT for 1 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 2 mg (22%). HPLC-MS: M+H=323; tR=1.65 min (*Method—1).
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1nccc2ccc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2ccnc(Cl)c2c1

Procedure:
A solution of 1-Methoxy-7-(trifluoromethyl)isoquinoline (50 mg, 0.22 mmol) from above step B in phosphorus oxychloride (1 mL) was heated at 150° C. for 18 h. Phosphorus oxychloride was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: ClN1[C:6](=[O:7])CCC1=O.[CH2:9]1[CH:18]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH:10]1[CH2:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:22].CO>C(Cl)(Cl)Cl>[CH2:9]1[CH:18]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH:10]1[CH2:19][O:20][C:21]([C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[O:7][CH3:6])=[O:22]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1[nH]c2ccccc2c1C(=O)OCC1CCN2CCCCC2C1
Reaction time: 2 h

Procedure:
A stirred solution of N-chlorosuccinimide (220 mg, 0.0016 mole) in chloroform (6 ml) at room temperature under nitrogen was treated with a solution of eq-quinolizidin-2-ylmethylindole-3-carboxylate (E9b) (330 mg, 0.0011 mole) in chloroform (6 ml) and stirred for 2 h. The solution was then treated with methanol (0.71 ml, 0.022 mole) and stirring continued. After 3 h a beige precipitate began to form and afar a further 1 h this was filtered off, washed with chloroform,and dried to afford the title compound (E26) as its hydrochloride salt mp 212°-213° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH2:25])=[N:22][C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([NH:25][CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])=[N:22][C:21]=2[CH:26]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Nc1nc2cc(Cl)ccc2s1
Product: CC1(C)Oc2ccc(C#N)cc2C(Nc2nc3cc(Cl)ccc3s2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzothiazol-2-ylamine as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1([C:22]([NH2:24])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[CH:25](OCC)(OCC)OCC>>[CH2:15]([N:12]1[CH2:11][CH2:10][C:9]2([N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[CH:25]=[N:24][C:22]2=[O:23])[CH2:14][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccccc1NC1(C(N)=O)CCN(Cc2ccccc2)CC1
Product: Cc1ccccc1N1C=NC(=O)C12CCN(Cc1ccccc1)CC2
Temperature: 150 °C
Reaction time: 240 h

Procedure:
4-(2-methyl-phenyl-amino)-1-(phenylmethyl)-4-piperidine-carboxamide (10.35 g) was dissolved in 60 ml triethyl orthoformate and stirred at 150° C. for 10 d. After cooling to 0° C, the reaction mixture was evaporated and the resulting brown oil was chromatographed on silica gel using dichloromethane:methanol 19:1 as eluent. 8-benzyl-1-(2-methyl-phenyl)-1,3,8-triazaspiro[4,5]dec-2-en-4-one (4.71 g) was obtained as a brown foam. MS: m/z=334 (M+H)+
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].ClCC(C1C=CC=CC=1)=O>>[Br:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Agent: O=C(CCl)c1ccccc1
Product: O[C@H](CBr)c1ccccc1
Yield: 55.4 %

Procedure:
The procedure as in Example 3 was repeated except that 7.5 g of 2-bromo-acetophenone was employed as a substrate in place of 7.5 g of 2-chloro-acetophenone to give 4.2 g of (S)-2-bromo-1-phenyl ethanol (b.p. 85° C./0.5 mmHg). The product had a specific rotatory power [α]D25 +48.7° (C=1, chloroform) and an optical purity of 97% enantiomer excess by an HPLC analysis.
Reaction SMILES: Br.Br[CH2:3][C:4]1[S:8][CH:7]=[N:6][C:5]=1[CH:9]=[CH2:10].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[CH:9]([C:5]1[N:6]=[CH:7][S:8][C:4]=1[CH2:3][S:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=1)=[CH2:10]
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: C=Cc1ncsc1CBr
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1ncsc1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a 0° C. mixture of 5-(bromomethyl)-4-ethenyl-1,3-thiazole hydrobromide (2.6 mmol) and 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (275 mg, 1.4 mmol) in absolute ethanol (15 mL) was added triethylamine (1.5 mL, 10.8 mmol). The mixture was stirred at room temperature overnight. The solution was evaporated, and the residue was treated with diethyl ether (100 mL). The solid material was removed by filtration. The filtrate was evaporated, and the crude product was purified by flash chromatography (0-5% MeOH/DCM), affording 2-{[(4-ethenyl-1,3-thiazol-5-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (270 mg, 60%); 1H NMR (500 MHz, DMSO-d6): δ 4.75 (s, 2H), 5.42 (dd, 1H, J=2.3 Hz, 10.8 Hz), 6.06 (dd, 1H, J=2.3 Hz, 16.9 Hz), 6.68 (s, 1H), 8.95 (s, 1H); M+ 320.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].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.[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67](O)=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[C:39]([C:43]1[N:47]([CH2:48][CH:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[C:46]2[CH:55]=[CH:56][C:57]([S:59]([N:62]3[CH:66]=[CH:65][C:64]([C:67]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[O:68])=[CH:63]3)(=[O:61])=[O:60])=[CH:58][C:45]=2[N:44]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: NCC(F)F
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NCC(F)F)c3)ccc2n1CC1CCOCC1
Yield: 1.6 %

Procedure:
Following the same procedure in Example 31, method B, using 2,2-difluoroethylamine (138 mg, 1.7 mmol), N,N-diisopropylethylamine (0.8 ml, 4.4 mmol), HATU (646 mg, 1.7 mmol) and 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (1.1 mmol) in DMF (15 mL). The crude product was purified on LCMS using high pH column 40-70% acetonitrile gradient to afford 9 mg (2% yield) of the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.51 (m, 3 H), 1.51-1.58 (m, 2 H), 1.60 (s, 9 H), 3.22 (q, J=7.36 Hz, 1 H), 3.33 (d, J=2.93 Hz, 1 H), 3.62 (m, 1 H), 3.68-3.76 (m, 1 H), 3.90 (dd, J=10.64, 3.42 Hz, 2 H), 4.43 (d, J=7.42 Hz, 2 H), 5.90 (m, 1 H), 6.68 (dd, J=3.03, 1.46 Hz, 1 H), 7.30-7.34 (m, 1 H), 7.87 (s, 1 H), 7.90-7.99 (m, 2 H), 8.28 (s, 1 H); MS (APPI) (M+H)+=509.3.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=2)=[O:19])[CH2:3][CH2:2]1.C(O)(=O)C>O1CCOCC1.C(O)C.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[N:22]=2)=[O:19])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3=CCNCC3)cc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(Nc1cccc(C(F)(F)F)n1)Nc1ccnc2ccc(C3CCNCC3)cc12
Reaction time: 7 h
Yield: 334.3 %

Procedure:
0.59 g of 1-(6-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-4-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)urea (0.427 mmol) were dissolved in a mixture of 143 ml of dioxane and 10 ml of ethanol. After addition of 0.152 g of Pd/C (1.427 mmol) and 0.082 ml of acetic acid (1.427 mmol), hydrogenation was performed for 7 h at 60° C. and over night at room temperature, which led to complete double bond hydrogenation according to HPLC/MSD analysis. The catalyst was filtered off, the solvent removed under reduced pressure and the residue extracted three times with ethyl acetate after adding water and a small amount of NaOH (pH 9). The combined organic phases were washed with a small amount of brine, dried over sodium sulfate and the solvent was removed under reduced pressure. 593 mg of the desired product were obtained as light yellow powder (yield: 64%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(O)C>C(Cl)(Cl)Cl>[CH:12]1[C:20]2[C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:9])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=S1c2ccccc2-c2ccccc21
Temperature: -35 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of mCPBA (8.27 g, 36.9 mmol) in 71 mL chloroform was added dropwise over 30 minutes to a solution of dibenzothiophene in 89 mL chloroform at −35° C. The reaction mixture was stirred at −35° C. for 1 hour and then warmed up to room. The reaction was quenched with saturated sodium bicarbonate aqueous solution. The organic layer was washed with saturated sodium bicarbonate solution twice and dried over MgSO4, concentrated down to give an off-white solid. The solid was dissolved in refluxing ethanol and slowly cooled to room temperature to give a white crystalline solid Dibenzothiophene 5-oxide (5.65 g, 76%). LCMS-ES: calc'd for C12H8OS: 200.26. Found: 200.9 (M+H+).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH:14][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Product: CCOC(=O)C(=CNc1ccc2c(c1)N1CCCN=C1S2)C(=O)OCC
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 5.13 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine and 6.5 parts of diethyl 2-(ethoxymethylene)propanedioate is stirred for 30 minutes at 100°-110° C. The product solidifies on triturating in 1,1'-oxybisethane, yielding 9 parts (96%) of diethyl 2-[(3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-yl)aminomethylene]propanedioate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:11]([S-:14])[CH2:12][CH3:13].[Na+]>>[Br:8][C:6]1[CH:7]=[C:2]([S:14][CH2:11][CH2:12][CH3:13])[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=1
Reactant: CCC[S-]
Reactant: COc1cc(Br)cc(Br)c1
Agent: [Na+]
Product: CCCSc1cc(Br)cc(OC)c1
Yield: 38.6 %

Procedure:
A similar procedure as described in Example 47, step 2 was used, starting from 3,5-dibromoanisole (5.3 g, 19.93 mmol) and sodium 1-propanethiolate (2.47 g, 23.92 mmol) to afford 1-bromo-3-methoxy-5-propylsulfanyl-benzene (2.01 g, 39%) as a light yellow oil: EI(+)-HRMS m/e calcd for C10H13BrOS (M)+ 259.9870, found 259.9870.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([S:11]([NH:14][O:15][CH3:16])(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.O>CN(C=O)C>[CH3:16][O:15][N:14]([S:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)(=[O:12])=[O:13])[C:23]1[CH:22]=[CH:21][C:20]([N+:25]([O-:27])=[O:26])=[CH:19][C:18]=1[Cl:17]
Reactant: CONS(=O)(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a suspension of sodium hydride (60%, 0.09 g (2.25 mmol)) in 3.0 ml of DMF, 3,4-dichloro-N-methoxybenzenesulfonamide (0.56 g (2.19 mmol)) was added with stirring under cooling with ice. To the resulting mixture, after 15 minutes' stirring under cooling with ice, 3-chloro-4-fluoronitrobenzene (0.35 ml (1.99 mmol)) was added and the mixture was stirred for one hour under cooling with ice and 3 hours at room temperature. Then, water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed twice with water and the ether layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 0.56 g (68%) of the title compound as pale yellow-white crystals.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[O:12]1[CH:14]([CH3:15])[CH2:13]1>>[OH:12][CH:14]([CH3:15])[CH2:13][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC1CO1
Product: CC(O)CNc1cccc(C(F)(F)F)c1
Yield: 61.5 %

Procedure:
3-Trifluoromethylaniline is reacted with 1,2-epoxy-propane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-3-trifluoromethyl-aniline with a yield of 61.5%; b.p.: 112°-118° C./0.5 mm Hg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36](Cl)=[CH:37][CH:38]=1)(=[O:33])=[O:32]>>[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][NH:30][S:31]([C:34]1[S:35][C:36]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:37][CH:38]=1)(=[O:33])=[O:32]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Cl)s1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.39) (134 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (32 mg, 11%). MS (ISN) 586.1 [(M−H)−]; mp 178° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:16]Br>C(O)(=O)C>[NH2:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[C:7]([Br:16])[CH:6]=2
Reactant: Nc1c(C(=O)O)cc2ccccc2c1Cl
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c(C(=O)O)cc2cc(Br)ccc2c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a mixture of 0.56 g of 3-amino-4-chloro-2-naphthoic acid and 20 ml of acetic acid was added dropwise 0.4 g of bromine at room temperature. The resulting mixture was stirred at room temperature for 1 hour. A deposited precipitate was collected by filtration, and the resulting solid was washed successively with acetic acid and ethyl acetate to obtain 0.36 g of 3-amino-7-bromo-4-chloro-2-naphthoic acid of the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH3:18])[C:13]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH3:18])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1c(-c2ccccc2OC)nnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1nnn(C)c1C(=O)O
Reaction time: 2 h
Yield: 95 %

Procedure:
To a soln. of methyl 4-(2-methoxyphenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylate (183 mg, 0.74 mmol) in MeOH (5 ml) was added sodium hydroxide (1.3 ml, 3M aq. solution). The mixture was stirred at r.t for 2 hrs, then concentrated in vacuo. The residue was taken up in water, washed w/ether (3×) to remove the possible impurity. The aq. phase was acidified w/6M HCl to pH 3, extracted w/EtOAc (4×). The combined organic layer was dried and evaporated to afford the title compound (164 mg, 0.703 mmol, 95% yield). 1H-NMR (500 MHz, CD3OD), δ: 7.46-7.42 (m, 2H), 7.09-7.05 (m, 2H), 4.32 (s, 3H), 3.73 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8]O)[N:5]([CH3:10])[N:4]=1)[CH3:2].P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:12][CH2:8][C:6]1[N:5]([CH3:10])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=1
Reactant: CCc1cc(CO)n(C)n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCc1cc(CBr)n(C)n1
Reaction time: 2 h

Procedure:
To a solution of compound 4 (500 mg, 3.57 mmol) in DCM (20 mL) was added PBr3 (386 mg, 1.43 mmol) was stirred at ° C. for 2 h. The mixture was washed with water, dried over Na2SO4. The solvent was evaporated to give the crude compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[I:18]N1C(=O)CCC1=O>C(#N)C.ClCCl>[I:18][C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[C:7]([C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=12
Reactant: COc1cc(-c2cnn(C)c2)cn2nccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(-c2cnn(C)c2)cn2ncc(I)c12
Reaction time: 1 h

Procedure:
4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine (486 mg, 2.13 mmol) was suspended in acetonitrile (30 ml). N-iodosuccinimide (958 mg, 4.26 mmol) was added and the mixture was allowed to stir for 1 h. The reaction mixture was diluted in dichloromethane, washed with water, 1N aqueous sodium hydroxide and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 3-iodo-4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine as a tan solid. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H); 8.28 (s, 1H); 8.01 (s, 1H); 7.92 (1, 1H); 6.89 (s, 1H); 3.96 (s, 3H); 3.85 (s, 3H). LRMS (ESI) calculated for C12H12IN4O [M+H]+, 355.0; found 354.9.