Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(COC)OC>[C:7]1([CH3:14])[CH:8]=[C:9]([CH3:13])[CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][CH2:3][C:2]([CH3:16])([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:15]
Reactant: Cc1cc(C)c(NC(=O)C(C)(C)Br)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Product: Cc1cc(C)c(NCC(C)(C)Nc2ccccc2)c(C)c1
Temperature: 25 °C

Procedure:
A solution of the amide (100 mg, 0.337 mmol) in dry dimethoxyethane (2 ml) was added lithium aluminum hydride (80 mg, 2.1 mmol), and the mixture was refluxed for 1 day. After cooling to room temperature, the reaction was quenched by adding H2O (0.08 ml), 15% aqueous NaOH (0.08 ml), and H2O (0.24 ml) successively. The white precipitation was filtered off and the filtrate was purified by column chromatography on silica (eluent: Hexane/Ethyl acetate=10/1) to give N1-mesityl-2-methyl-N2-phenylpropane-1,2-diamine as a pale yellow solid (54 mg, 0.192 mmol, Y=57%). The diamine (1.45 g, 5.14 mmol) was converted to the corresponding dihydrochloride salt (1.83 g, 5.14 mmol, 100%) by treating with HCl solution (4 M in dioxane). A mixture of this salt (500 mg, 1.4 mmol) and triethyl orthoformate (4.7 ml) was stirred at 130° C. for 5 min then cooled. After cooling to room temperature, the white precipitation was collected by filtration washing with large amount of diethyl ether and then with acetone to give the desired imidazolidinium chloride salt (367 mg, 1.12 mmol, Y=80%). 1H NMR (300 MHz, CDCl3): δ 9.76 (s, 1H), 7.65-7.62 (m, 2H), 7.49-7.47 (m, 3H), 6.92 (s, 2H), 4.13 (s, 2H), 2.39 (s, 6H), 2.27 (s, 3H), 1.69 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 158.4, 140.2, 134.9, 132.3, 130.2, 130.0, 129.9, 129.8, 127.4, 68.6, 63.7, 26.7, 20.9, 18.1. IR: 3401 (m), 2975 (w), 1624 (s), 1592 (m), 1301 (w), 1263 (m), 1219 (m), 856 (w), 776 (w) cm−1. HRMS Calc'd for C20H25N2: 293.2018. Meas: 293.2021.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4F)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (32 mg, 39%), MS (ISP) m/z=331.4 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20]Cl)[C:9]2=[O:22])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][S:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: O=C1C(CCCl)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1C(CCSc2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reaction time: 20 h

Procedure:
To a stirring solution of 1-(4-fluorophenyl)-3-(2-chloroethyl)-4-(4-hydroxyphenyl)azetidin-2-one (Method 12; 0.750 g, 2.35 mmol) in MeCN (10 ml) was added 4-fluorothiophenol (0.500 ml, 4.60 mmol) and triethylamine (0.500 ml, 3.59 mmol) at room temperature. After 20 hours there were still start materiel left (approximately 20%, LC/MS) and more 4-fluorothiophenol (0.250 ml, 2.30 mmol) and triethylamine (0.170 ml, 1.22 mmol) were added. After 24 hours, the solvent was removed under reduced pressure and the residue was partitioned between water (20 ml) and EtOAc (20 ml). The organic layer was washed with brine (5 ml), dried over magnesium sulphate and concentrated. The residue was refluxed in heptane for 30 minutes before the title compound was filtered off as a grey solid (0.946 g; 98%). NMR (CD3OD, 400 MHz) 2.00-2.20 (m, 2H), 3.05 (t, 2H), 3.25 (dt, 1H), 4.75 (d, 1H), 6.75-6.80 (m, 2H), 6.90-7.05 (m, 4H), 7.15-7.40 (m, 6H); m/z: 412.0.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[C:8]1([CH3:15])[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.[NH2:16][C:17]1[N:25]=[C:24](Cl)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Cl-].[Na+].O>[NH2:16][C:17]1[N:25]=[C:24]([S:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:15])=[CH:9][CH:10]=2)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Reactant: Cc1ccc(S)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2nc(N)c3ncn(Cc4ccccc4)c3n2)cc1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added p-toluenethiol (1.9 g, 15 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 100° C. for 3 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (124 mg, yield 93%).
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([CH3:12])[CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)#[CH:14]>>[CH3:12][C:4]1[CH:3]=[C:2]2[C:7](=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=1)[NH:8][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=1)=[CH:14]2
Reactant: C#Cc1cccc(C)n1
Reactant: Cc1cc(I)c(N)c([N+](=O)[O-])c1
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3cccc(C)n3)cc2c1
Yield: 35.3 %

Procedure:
6-Iodo-4-methyl-2-nitroaniline (500 mg, 1.8 mmol) and 2-ethinyl-6-methylpyridine (210 mg, 1.8 mmol) were reacted according to the same procedure as Preparation 19 to give the title compound (170 mg, Yield 35%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:16][C:6]2[CH2:7][CH2:8][N:9]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[S-:17][C:18]#[N:19].[K+].BrBr>>[NH2:19][C:18]1[S:17][C:4]2[C:5]3[CH2:11][CH2:10][N:9]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:8][CH2:7][C:6]=3[S:16][C:3]=2[N:2]=1
Reactant: N#C[S-]
Reactant: CCC(=O)N1CCc2cc(N)sc2CC1
Agent: BrBr
Agent: Cl
Agent: [K+]
Product: CCC(=O)N1CCc2sc3nc(N)sc3c2CC1

Procedure:
This compound was prepared from 2-amino-6-propionyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine hydrochloride, potassium thiocyanate and bromine analogous to Example 1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[N:23]=[CH:24][N:25]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=1)[C:3]([NH:5][C@@H:6]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:7]([OH:13])[C@H:8]([CH:10]1[CH2:12][CH2:11]1)[OH:9])=[O:4].[N:46]1[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[NH:48][C:47]=1[C:55](O)=[O:56].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(#N)C>[CH:15]1([CH2:14][C@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:55]([C:47]2[NH:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=3[N:46]=2)=[O:56])[CH2:21][C:22]2[N:23]=[CH:24][N:25]([C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]=2)=[O:4])[C@@H:7]([OH:13])[C@H:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87 %

Procedure:
A mixture of 355 mg (0.58 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-1-tritylimidazole-4-propionamide, 95 mg (0.58 mmol) of benzimidazole-2-carboxylic acid [Chem. Ber. 45, 3489 (1912)], 256 mg (0.58 mmol) of BOP and 0.12 ml (0.58 mmol) of Hunig base in 50 ml of acetonitrile is stirred at room temperature for 20 hours. Thereafter, the reaction mixture is evaporated under reduced pressure, the residue is taken up in 60 ml of ethyl acetate and washed twice with 20 ml of saturated potassium hydrogen carbonate solution. After drying the organic phase over sodium sulphate the solvent is evaporated under reduced pressure. For purification, the residue is chromatographed on 30 g of silica gel using a 15:1 mixture of methylene chloride and methanol as the eluent. There are obtained 379 mg of N-[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-(1-tritylimidazol-4-yl)ethyl]-2-benzimidazolecarboxamide as a colourless foam; MS: 751 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[C:10](=[O:20])[C:8]=2[N:9]=1)[CH3:4]>ClCCl.C(O)C>[CH2:3]([C:5]1[S:6][C:7]2[CH:14]=[CH:13][C:12]3[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=3[CH:10]([OH:20])[C:8]=2[N:9]=1)[CH3:4]
Reactant: CCc1nc2c(=O)c3ccc(C)cc3ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCc1nc2c(s1)C=Cc1cc(C)ccc1C2O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium borohydride (78 mg) was added to a stirred solution of the product from step (ii) (0.87 g) in dichloromethane (4 ml) and ethanol (16 ml) at 5° C. The reaction mixture was stirred for 2.5 h, warmed to room temperature and left for 2 h before a further 200 mg of sodium borohydride was added. The reaction mixture was quenched with 1M sodium hydroxide solution then partitioned between dichloromethane and water. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:22])C(=O)C1>C(#N)C>[Br:22][C:10]1[C:11]([NH2:14])=[N:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cn1
Solvent: CC#N
Product: Nc1ncc(-c2ccc(Cl)cc2)cc1Br

Procedure:
Prepared from crude 5-(4-chloro-phenyl)-pyridin-2-ylamine (example C.27 step 1) (ca. 50 mmol) in acetonitrile (100 mL) and NBS (9.34 g, 53 mmol) as described in example C.25 step 2. Obtained the crude 3-bromo-5-(4-chloro-phenyl)-pyridin-2-ylamine a dark brown solid (76% pure).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:28])=[C:6]([C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=1)[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[O:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:29]([O:28][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:23][C:22]([O:24][CH3:25])=[C:21]([O:26][CH3:27])[C:6]=1[CH2:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(C)=O)c(O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1cc(C(C)=O)c(OC(C)=O)c(CN2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
A solution of tert-butyl 4-(3-acetyl-2-hydroxy-5,6-dimethoxybenzyl)piperazine-1-carboxylate (0.20 g, 0.50 mmol) in pyridine (1.0 mL) was successively added with acetic anhydride (1.0 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was added with ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (2:1→3:7)) to obtain tert-butyl 4-(2-acetoxy-3-acetyl-5,6-dimethoxybenzyl)piperazine-1-carboxylate (0.15 g, 70%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[CH:36]=[CH:35][CH:34]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:32]=5[CH:31]=[CH:30][C:29]4=[O:42])[CH2:22][CH2:21]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To 0.2 mL of an ethyl acetate solution containing 9.0 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxycarbonyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature for 42 hours. The solvent was removed under reduced pressure to give 8.4 mg of methyl 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-1,2-dihydro-2-oxoquinoline-5-carboxylate hydrochloride as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[Cl:11][C:12]1[C:20]([F:21])=[CH:19][C:15]([C:16](O)=O)=[C:14]([F:22])[CH:13]=1.N>>[Cl:11][C:12]1[C:20]([F:21])=[CH:19][C:15]([C:16]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[C:14]([F:22])[CH:13]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)c(F)cc1Cl

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 4-chloro-2,5-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.73 (dd, J=9.7, 5.9 Hz, 1H), 8.18 (dd, J=8.8, 6.1 Hz, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.75 (dd, J=4.7, 1.7 Hz, 1H), 9.30 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 294 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)=[O:4].[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)=[CH:11][CH:10]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccc(I)cc2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccc([C@@H]3C[C@H]3N(CC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)C(F)(F)F)cc2)cn1
Temperature: 85 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a 10-mL microwave tube were added tert-butyl 4-((2,2,2-trifluoro-N-(trans-2-(4-iodophenyl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate (300 mg, 0.543 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (136 mg, 0.652 mmol), potassium carbonate (263 mg, 1.901 mmol), acetonitrile (2 mL) and water (0.500 mL), and the mixture was degassed by bubbling N2 through. Tetrakis (31.4 mg, 0.027 mmol) was added and the tube was sealed. The mixture was stirred at 85° C. for 4 h. The mixture was cooled and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 120 mg of product as pale yellow solid. MS: (M+H)+=507.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.08-1.20 (m, 2H), 1.43-1.54 (m, 10H), 1.57-1.78 (m, 3H), 1.95-2.10 (m, 2H), 2.40-2.86 (m, 3H), 3.16 (d, J=3.54 Hz, 1H), 3.38-3.63 (m, 2H), 3.90-3.98 (m, 3H), 4.00-4.19 (m, 2H), 7.09-7.18 (m, 2H), 7.46-7.55 (m, 2H), 7.77-7.84 (m, 1H), 7.90-7.97 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:9]([CH2:10]O)=[C:8]([CH2:12][O:13][CH3:14])[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:5]=2)[CH2:3][CH2:2]1.S(Cl)([Cl:27])=O>ClCCl>[Cl:27][CH2:10][C:9]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][C:6]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=2)=[N:7][C:8]=1[CH2:12][O:13][CH3:14]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A solution of 1.29 g (3.8 mmol) [4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol in 12 ml dichloromethane was treated with 0.29 ml (3.99 mmol) thionylchloride. After 2 h stirring at RT, the mixture was partitioned between ether and water. The ether-phase was concentrated under reduced pressure giving 1.35 g pure crystalline 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][C:6]1=[O:17].[CH3:18][O:19][CH2:20][CH2:21][OH:22]>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:6]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[O:7][CH2:2][CH2:3][CH2:4]1)=[O:17]
Reactant: COCCO
Reactant: O=c1oc2cc([N+](=O)[O-])ccc2n1CCCCl
Product: COCCOC(=O)N1CCCOc2cc([N+](=O)[O-])ccc21

Procedure:
3-Nitro-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 2-methoxy-ethyl ester was prepared from 3-(3-chloro-propyl)-6-nitro-3H-benzoxazol-2-one and 2-methoxyethanol in an analogous manner to Example 1426a. Product isolated as a yellow oil (175 mg, 25%). LCMS (m/e) 297 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.89-7.83 (m, 2H), 7.57-7.42 (m, 1H), 4.43-4.20 (m, 4H), 3.95-3.81 (m, 2H), 3.70-3.54 (m, 2H), 3.38 (s, 3H), 2.23-2.12 (m, 2H).
Reaction SMILES: [CH:1]([NH:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)=O.[C:21](=O)([O-])[O-:22].[K+].[K+].CI>CN(C)C=O>[CH:21]([CH2:1][NH:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5]1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn(NC=O)c2nc(C)ccc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(NCC=O)c2nc(C)ccc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-(formylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate (11.8 g, 0.043 m) was added to a stirred mixture of 20.3 g (0.136 m) of anhydrous, milled potassium carbonate and 103 ml of dimethylformamide. The mixture was stirred for 30 minutes, and 20.3 ml (0.33 m) of methyl iodide was then added. The reaction mixture was stirred for five hours on a steam bath, then at room temperature overnight, and poured into 400 ml of ice-water. The solid product was collected by filtration, washed with water, and dried at 60° C. in vacuo to give 8.1 g of ethyl 1-(N-formylmethylamino)-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, beige solid, m.p. 210°-212° C.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[N:9][C:8]=2[CH:16]=1.[Na]>>[NH2:9][CH2:8][CH2:7][S:11][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][C:13]([NH2:15])=[NH:14])=[N:9][C:8]=2[CH:16]=1
Reactant: N=C(N)Nc1nc2cc(CBr)ccc2s1
Agent: Br
Agent: [Na]
Product: N=C(N)Nc1nc2cc(CSCCN)ccc2s1
Temperature: 25 °C

Procedure:
Cysteamine.hydrochloride (0.4 g) was caused to react with sodium ethoxide in ethanol to yield a sodium salt. Then, 5-bromomethyl-2-guanidinobenzothiazole.hydrobromide (0.63 g) was added to the sodium salt at an internal temperature of 0° C. After agitating the mixture over one night at room temperature, the solvent was removed, and the residue was made acidic with addition of dilute hydrochloric acid. The crystalline precipitate was collected to obtain 5-[(2-aminoethyl)thiomethyl]-2-guanidinobenzothiazole.2hydrochloride (0.5 g).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:26]([CH3:34])([CH2:27][CH2:28][C:29]=32)[C@@H:18]([C@H:19]([CH3:25])[CH2:20][CH2:21][C:22]([OH:24])=O)[CH2:17][CH:16]=4)[C:10]1([CH3:36])[CH3:35])(C(C)(C)C)(C)C.[C:37]([NH2:41])([CH3:40])([CH3:39])[CH3:38].Cl.C(O)C>>[C:37]([NH:41][C:22](=[O:24])[CH2:21][CH2:20][C@H:19]([C@@H:18]1[C@:26]2([CH3:34])[C:15]([C:14]3[CH2:13][CH2:12][C@@H:11]4[C@:30]([C:29]=3[CH2:28][CH2:27]2)([CH3:33])[CH2:31][CH2:32][C@H:9]([OH:8])[C:10]4([CH3:35])[CH3:36])=[CH:16][CH2:17]1)[CH3:25])([CH3:40])([CH3:39])[CH3:38]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCO
Product: C[C@H](CCC(=O)NC(C)(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-oic acid (0.50 g) is reacted with tert-butylamine and hydrolysed with HCl/ethanol following the procedure outlined in example 39 to give the title compound (204 mg). Melting point: 171-176° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:39])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH3:38])[OH:13])[C:6]=2[N:7]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:39])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH3:38])[OH:13])[C:6]=2[N:7]=1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To a solution of the product from Step A (630 mg, 1.0 mmol) in CH2Cl2 (20 mL) at −78° C. was added boron trichloride (1M in CH2Cl2) (10 mL, 10 mmol). The mixture was stirred at −78° C. for 2 h, then at −20° C. for 2.5 h. The reaction was quenched with CH2Cl2MeOH (1:1) (10 mL), stirred at −20° C. for 0.5 h, and neutralized at 0° C. with aqueous ammonia. The solid was filtered, washed with CH2Cl2/MeOH (1:1) and the combined filtrate evaporated in vacuo. The residue was purified on a silica gel column with CH2Cl2/MeOH, 50/1 and 20/1 as eluent to give the title compound as a colorless foam (250 mg).